Sample records for designed templating ligand
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Webb, Thomas R; Jiang, Luyong; Sviridov, Sergey; Venegas, Ruben E; Vlaskina, Anna V; McGrath, Douglas; Tucker, John; Wang, Jian; Deschenes, Alain; Li, Rongshi
2007-01-01
We report the further application of a novel approach to template and ligand design by the synthesis of agonists of the melanocortin receptor. This design method uses the conserved structural data from the three-dimensional conformations of beta-turn peptides to design rigid nonpeptide templates that mimic the orientation of the main chain C-alpha atoms in a peptide beta-turn. We report details on a new synthesis of derivatives of template 1 that are useful for the synthesis of exploratory libraries. The utility of this technique is further exemplified by several iterative rounds of high-throughput synthesis and screening, which result in new partially optimized nonpeptide agonists for several melanocortin receptors.
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Su, Bo-Han; Huang, Yi-Syuan; Chang, Chia-Yun; Tu, Yi-Shu; Tseng, Yufeng J
2013-10-31
There is a compelling need to discover type II inhibitors targeting the unique DFG-out inactive kinase conformation since they are likely to possess greater potency and selectivity relative to traditional type I inhibitors. Using a known inhibitor, such as a currently available and approved drug or inhibitor, as a template to design new drugs via computational de novo design is helpful when working with known ligand-receptor interactions. This study proposes a new template-based de novo design protocol to discover new inhibitors that preserve and also optimize the binding interactions of the type II kinase template. First, sorafenib (Nexavar) and nilotinib (Tasigna), two type II inhibitors with different ligand-receptor interactions, were selected as the template compounds. The five-step protocol can reassemble each drug from a large fragment library. Our procedure demonstrates that the selected template compounds can be successfully reassembled while the key ligand-receptor interactions are preserved. Furthermore, to demonstrate that the algorithm is able to construct more potent compounds, we considered kinase inhibitors and other protein dataset, acetylcholinesterase (AChE) inhibitors. The de novo optimization was initiated using a template compound possessing a less than optimal activity from a series of aminoisoquinoline and TAK-285 inhibiting type II kinases, and E2020 derivatives inhibiting AChE respectively. Three compounds with greater potency than the template compound were discovered that were also included in the original congeneric series. This template-based lead optimization protocol with the fragment library can help to design compounds with preferred binding interactions of known inhibitors automatically and further optimize the compounds in the binding pockets.
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Schüller, Andreas; Suhartono, Marcel; Fechner, Uli; Tanrikulu, Yusuf; Breitung, Sven; Scheffer, Ute; Göbel, Michael W; Schneider, Gisbert
2008-02-01
Principles of fragment-based molecular design are presented and discussed in the context of de novo drug design. The underlying idea is to dissect known drug molecules in fragments by straightforward pseudo-retro-synthesis. The resulting building blocks are then used for automated assembly of new molecules. A particular question has been whether this approach is actually able to perform scaffold-hopping. A prospective case study illustrates the usefulness of fragment-based de novo design for finding new scaffolds. We were able to identify a novel ligand disrupting the interaction between the Tat peptide and TAR RNA, which is part of the human immunodeficiency virus (HIV-1) mRNA. Using a single template structure (acetylpromazine) as reference molecule and a topological pharmacophore descriptor (CATS), new chemotypes were automatically generated by our de novo design software Flux. Flux features an evolutionary algorithm for fragment-based compound assembly and optimization. Pharmacophore superimposition and docking into the target RNA suggest perfect matching between the template molecule and the designed compound. Chemical synthesis was straightforward, and bioactivity of the designed molecule was confirmed in a FRET assay. This study demonstrates the practicability of de novo design to generating RNA ligands containing novel molecular scaffolds.
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Ligand Binding Site Detection by Local Structure Alignment and Its Performance Complementarity
Lee, Hui Sun; Im, Wonpil
2013-01-01
Accurate determination of potential ligand binding sites (BS) is a key step for protein function characterization and structure-based drug design. Despite promising results of template-based BS prediction methods using global structure alignment (GSA), there is a room to improve the performance by properly incorporating local structure alignment (LSA) because BS are local structures and often similar for proteins with dissimilar global folds. We present a template-based ligand BS prediction method using G-LoSA, our LSA tool. A large benchmark set validation shows that G-LoSA predicts drug-like ligands’ positions in single-chain protein targets more precisely than TM-align, a GSA-based method, while the overall success rate of TM-align is better. G-LoSA is particularly efficient for accurate detection of local structures conserved across proteins with diverse global topologies. Recognizing the performance complementarity of G-LoSA to TM-align and a non-template geometry-based method, fpocket, a robust consensus scoring method, CMCS-BSP (Complementary Methods and Consensus Scoring for ligand Binding Site Prediction), is developed and shows improvement on prediction accuracy. The G-LoSA source code is freely available at http://im.bioinformatics.ku.edu/GLoSA. PMID:23957286
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New Human CD22/Siglec-2 Ligands with a Triazole Glycoside.
Prescher, Horst; Schweizer, Astrid; Kuhfeldt, Elena; Nitschke, Lars; Brossmer, Reinhard
2017-07-04
CD22 is a member of the Siglec family. Considerable attention has been drawn to the design and synthesis of new Siglec ligands to explore target biology and innovative therapies. In particular, CD22-ligand-targeted nanoparticles with therapeutic functions have proved successful in preclinical settings for blood cancers, autoimmune diseases, and tolerance induction. Here we report the design, synthesis and affinity evaluation of a new class of Siglec ligands: namely sialic acid derivatives with a triazole moiety replacing the natural glycoside oxygen atom. In addition, we describe important and surprising differences in binding to CD22 expressed at the cell surface for compounds with distinct valences. The new class of compounds might serve as a template for the design of ligands for other members of the Siglec family and next-generation CD22-ligand-based targeted therapies. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Song, Jie; Viengkham, Malathong; Bertozzi, Carolyn R.
The controlled integration of organic and inorganic components confers natural bone with superior mechanical properties. Bone biogenesis is thought to occur by templated mineralization of hard apatite crystals by an elastic protein scaffold, a process we sought to emulate with synthetic biomimetic hydrogel polymers. Crosslinked polymethacrylamide and polymethacrylate hydrogels were functionalized with mineral-binding ligands and used to template the formation of hydroxyapatite. Strong adhesion between the organic and inorganic materials was achieved for hydrogels functionalized with either carboxylate or hydroxy ligands. The mineral-nucleating potential of hydroxyl groups identified here broadens the design parameters for synthetic bone-like composites and suggests amore » potential role for hydroxylated collagen proteins in bone mineralization.« less
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Multistate approaches in computational protein design
Davey, James A; Chica, Roberto A
2012-01-01
Computational protein design (CPD) is a useful tool for protein engineers. It has been successfully applied towards the creation of proteins with increased thermostability, improved binding affinity, novel enzymatic activity, and altered ligand specificity. Traditionally, CPD calculations search and rank sequences using a single fixed protein backbone template in an approach referred to as single-state design (SSD). While SSD has enjoyed considerable success, certain design objectives require the explicit consideration of multiple conformational and/or chemical states. Cases where a “multistate” approach may be advantageous over the SSD approach include designing conformational changes into proteins, using native ensembles to mimic backbone flexibility, and designing ligand or oligomeric association specificities. These design objectives can be efficiently tackled using multistate design (MSD), an emerging methodology in CPD that considers any number of protein conformational or chemical states as inputs instead of a single protein backbone template, as in SSD. In this review article, recent examples of the successful design of a desired property into proteins using MSD are described. These studies employing MSD are divided into two categories—those that utilized multiple conformational states, and those that utilized multiple chemical states. In addition, the scoring of competing states during negative design is discussed as a current challenge for MSD. PMID:22811394
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In silico design of ligand triggered RNA switches.
Findeiß, Sven; Hammer, Stefan; Wolfinger, Michael T; Kühnl, Felix; Flamm, Christoph; Hofacker, Ivo L
2018-04-13
This contribution sketches a work flow to design an RNA switch that is able to adapt two structural conformations in a ligand-dependent way. A well characterized RNA aptamer, i.,e., knowing its K d and adaptive structural features, is an essential ingredient of the described design process. We exemplify the principles using the well-known theophylline aptamer throughout this work. The aptamer in its ligand-binding competent structure represents one structural conformation of the switch while an alternative fold that disrupts the binding-competent structure forms the other conformation. To keep it simple we do not incorporate any regulatory mechanism to control transcription or translation. We elucidate a commonly used design process by explicitly dissecting and explaining the necessary steps in detail. We developed a novel objective function which specifies the mechanistics of this simple, ligand-triggered riboswitch and describe an extensive in silico analysis pipeline to evaluate important kinetic properties of the designed sequences. This protocol and the developed software can be easily extended or adapted to fit novel design scenarios and thus can serve as a template for future needs. Copyright © 2018. Published by Elsevier Inc.
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PoLi: A Virtual Screening Pipeline Based On Template Pocket And Ligand Similarity
Roy, Ambrish; Srinivasan, Bharath; Skolnick, Jeffrey
2015-01-01
Often in pharmaceutical research, the goal is to identify small molecules that can interact with and appropriately modify the biological behavior of a new protein target. Unfortunately, most proteins lack both known structures and small molecule binders, prerequisites of many virtual screening, VS, approaches. For such proteins, ligand homology modeling, LHM, that copies ligands from homologous and perhaps evolutionarily distant template proteins, has been shown to be a powerful VS approach to identify possible binding ligands. However, if we want to target a specific pocket for which there is no homologous holo template protein structure, then LHM will not work. To address this issue, in a new pocket based approach, PoLi, we generalize LHM by exploiting the fact that the number of distinct small molecule ligand binding pockets in proteins is small. PoLi identifies similar ligand binding pockets in a holo-template protein library, selectively copies relevant parts of template ligands and uses them for VS. In practice, PoLi is a hybrid structure and ligand based VS algorithm that integrates 2D fingerprint-based and 3D shape-based similarity metrics for improved virtual screening performance. On standard DUD and DUD-E benchmark databases, using modeled receptor structures, PoLi achieves an average enrichment factor of 13.4 and 9.6 respectively, in the top 1% of the screened library. In contrast, traditional docking based VS using AutoDock Vina and homology-based VS using FINDSITEfilt have an average enrichment of 1.6 (3.0) and 9.0 (7.9) on the DUD (DUD-E) sets respectively. Experimental validation of PoLi predictions on dihydrofolate reductase, DHFR, using differential scanning fluorimetry, DSF, identifies multiple ligands with diverse molecular scaffolds, thus demonstrating the advantage of PoLi over current state-of-the-art VS methods. PMID:26225536
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Predicting the accuracy of ligand overlay methods with Random Forest models.
Nandigam, Ravi K; Evans, David A; Erickson, Jon A; Kim, Sangtae; Sutherland, Jeffrey J
2008-12-01
The accuracy of binding mode prediction using standard molecular overlay methods (ROCS, FlexS, Phase, and FieldCompare) is studied. Previous work has shown that simple decision tree modeling can be used to improve accuracy by selection of the best overlay template. This concept is extended to the use of Random Forest (RF) modeling for template and algorithm selection. An extensive data set of 815 ligand-bound X-ray structures representing 5 gene families was used for generating ca. 70,000 overlays using four programs. RF models, trained using standard measures of ligand and protein similarity and Lipinski-related descriptors, are used for automatically selecting the reference ligand and overlay method maximizing the probability of reproducing the overlay deduced from X-ray structures (i.e., using rmsd < or = 2 A as the criteria for success). RF model scores are highly predictive of overlay accuracy, and their use in template and method selection produces correct overlays in 57% of cases for 349 overlay ligands not used for training RF models. The inclusion in the models of protein sequence similarity enables the use of templates bound to related protein structures, yielding useful results even for proteins having no available X-ray structures.
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Protein-Templated Fragment Ligations-From Molecular Recognition to Drug Discovery.
Jaegle, Mike; Wong, Ee Lin; Tauber, Carolin; Nawrotzky, Eric; Arkona, Christoph; Rademann, Jörg
2017-06-19
Protein-templated fragment ligation is a novel concept to support drug discovery and can help to improve the efficacy of protein ligands. Protein-templated fragment ligations are chemical reactions between small molecules ("fragments") utilizing a protein's surface as a reaction vessel to catalyze the formation of a protein ligand with increased binding affinity. The approach exploits the molecular recognition of reactive small-molecule fragments by proteins both for ligand assembly and for the identification of bioactive fragment combinations. In this way, chemical synthesis and bioassay are integrated in one single step. This Review discusses the biophysical basis of reversible and irreversible fragment ligations and gives an overview of the available methods to detect protein-templated ligation products. The chemical scope and recent applications as well as future potential of the concept in drug discovery are reviewed. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Litfin, Thomas; Zhou, Yaoqi; Yang, Yuedong
2017-04-15
The high cost of drug discovery motivates the development of accurate virtual screening tools. Binding-homology, which takes advantage of known protein-ligand binding pairs, has emerged as a powerful discrimination technique. In order to exploit all available binding data, modelled structures of ligand-binding sequences may be used to create an expanded structural binding template library. SPOT-Ligand 2 has demonstrated significantly improved screening performance over its previous version by expanding the template library 15 times over the previous one. It also performed better than or similar to other binding-homology approaches on the DUD and DUD-E benchmarks. The server is available online at http://sparks-lab.org . yaoqi.zhou@griffith.edu.au or yuedong.yang@griffith.edu.au. Supplementary data are available at Bioinformatics online. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com
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Weiss, Dahlia R; Ahn, SeungKirl; Sassano, Maria F; Kleist, Andrew; Zhu, Xiao; Strachan, Ryan; Roth, Bryan L; Lefkowitz, Robert J; Shoichet, Brian K
2013-05-17
A prospective, large library virtual screen against an activated β2-adrenergic receptor (β2AR) structure returned potent agonists to the exclusion of inverse-agonists, providing the first complement to the previous virtual screening campaigns against inverse-agonist-bound G protein coupled receptor (GPCR) structures, which predicted only inverse-agonists. In addition, two hits recapitulated the signaling profile of the co-crystal ligand with respect to the G protein and arrestin mediated signaling. This functional fidelity has important implications in drug design, as the ability to predict ligands with predefined signaling properties is highly desirable. However, the agonist-bound state provides an uncertain template for modeling the activated conformation of other GPCRs, as a dopamine D2 receptor (DRD2) activated model templated on the activated β2AR structure returned few hits of only marginal potency.
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NASA Astrophysics Data System (ADS)
Duan, Rui; Xu, Xianjin; Zou, Xiaoqin
2018-01-01
D3R 2016 Grand Challenge 2 focused on predictions of binding modes and affinities for 102 compounds against the farnesoid X receptor (FXR). In this challenge, two distinct methods, a docking-based method and a template-based method, were employed by our team for the binding mode prediction. For the new template-based method, 3D ligand similarities were calculated for each query compound against the ligands in the co-crystal structures of FXR available in Protein Data Bank. The binding mode was predicted based on the co-crystal protein structure containing the ligand with the best ligand similarity score against the query compound. For the FXR dataset, the template-based method achieved a better performance than the docking-based method on the binding mode prediction. For the binding affinity prediction, an in-house knowledge-based scoring function ITScore2 and MM/PBSA approach were employed. Good performance was achieved for MM/PBSA, whereas the performance of ITScore2 was sensitive to ligand composition, e.g. the percentage of carbon atoms in the compounds. The sensitivity to ligand composition could be a clue for the further improvement of our knowledge-based scoring function.
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Terry, Tracy J.; Stack, T. Daniel P.
2009-01-01
Considerable attention has been devoted to the immobilization of discrete epoxidation catalysts onto solid supports due to the possible benefits of site isolation such as increased catalyst stability, catalyst recycling, and product separation. A synthetic metal-template/metal-exchange method to imprint a covalently attached bis-1,10-phenanthroline coordination environment onto high-surface area, mesoporous SBA-15 silica is reported herein along with the epoxidation reactivity once reloaded with manganese. Comparisons of this imprinted material with material synthesized by random grafting of the ligand show that the template method creates more reproducible, solution-like bis-1,10-phenanthroline coordination at a variety of ligand loadings. Olefin epoxidation with peracetic acid shows the imprinted manganese catalysts have improved product selectivity for epoxides, greater substrate scope, more efficient use of oxidant, and higher reactivity than their homogeneous or grafted analogues independent of ligand loading. The randomly grafted manganese catalysts, however, show reactivity that varies with ligand loading while the homogeneous analogue degrades trisubstituted olefins and produces trans-epoxide products from cis-olefins. Efficient recycling behavior of the templated catalysts is also possible. PMID:18351763
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NASA Astrophysics Data System (ADS)
Zavodszky, Maria I.; Sanschagrin, Paul C.; Kuhn, Leslie A.; Korde, Rajesh S.
2002-12-01
For the successful identification and docking of new ligands to a protein target by virtual screening, the essential features of the protein and ligand surfaces must be captured and distilled in an efficient representation. Since the running time for docking increases exponentially with the number of points representing the protein and each ligand candidate, it is important to place these points where the best interactions can be made between the protein and the ligand. This definition of favorable points of interaction can also guide protein structure-based ligand design, which typically focuses on which chemical groups provide the most energetically favorable contacts. In this paper, we present an alternative method of protein template and ligand interaction point design that identifies the most favorable points for making hydrophobic and hydrogen-bond interactions by using a knowledge base. The knowledge-based protein and ligand representations have been incorporated in version 2.0 of SLIDE and resulted in dockings closer to the crystal structure orientations when screening a set of 57 known thrombin and glutathione S-transferase (GST) ligands against the apo structures of these proteins. There was also improved scoring enrichment of the dockings, meaning better differentiation between the chemically diverse known ligands and a ˜15,000-molecule dataset of randomly-chosen small organic molecules. This approach for identifying the most important points of interaction between proteins and their ligands can equally well be used in other docking and design techniques. While much recent effort has focused on improving scoring functions for protein-ligand docking, our results indicate that improving the representation of the chemistry of proteins and their ligands is another avenue that can lead to significant improvements in the identification, docking, and scoring of ligands.
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Shoravi, Siamak; Olsson, Gustaf D; Karlsson, Björn C G; Nicholls, Ian A
2014-06-12
Aspects of the molecular-level basis for the function of ethylene glycol dimethacrylate and trimethylolproprane trimethacrylate crosslinked methacrylic acid copolymers molecularly imprinted with (S)-propranolol have been studied using a series of all-component and all-atom molecular dynamics studies of the corresponding prepolymerization systems. The crosslinking agents were observed to contribute to template complexation, and the results were contrasted with previously reported template-recognition behavior of the corresponding polymers. Differences in the extent to which the two crosslinkers interacted with the functional monomer were identified, and correlations were made to polymer-ligand recognition behavior and the results of nuclear magnetic resonance spectroscopic studies studies. This study demonstrates the importance of considering the functional monomer-crosslinker interaction when designing molecularly imprinted polymers, and highlights the often neglected general contribution of crosslinker to determining the nature of molecularly imprinted polymer-template selectivity.
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Concept of combinatorial de novo design of drug-like molecules by particle swarm optimization.
Hartenfeller, Markus; Proschak, Ewgenij; Schüller, Andreas; Schneider, Gisbert
2008-07-01
We present a fast stochastic optimization algorithm for fragment-based molecular de novo design (COLIBREE, Combinatorial Library Breeding). The search strategy is based on a discrete version of particle swarm optimization. Molecules are represented by a scaffold, which remains constant during optimization, and variable linkers and side chains. Different linkers represent virtual chemical reactions. Side-chain building blocks were obtained from pseudo-retrosynthetic dissection of large compound databases. Here, ligand-based design was performed using chemically advanced template search (CATS) topological pharmacophore similarity to reference ligands as fitness function. A weighting scheme was included for particle swarm optimization-based molecular design, which permits the use of many reference ligands and allows for positive and negative design to be performed simultaneously. In a case study, the approach was applied to the de novo design of potential peroxisome proliferator-activated receptor subtype-selective agonists. The results demonstrate the ability of the technique to cope with large combinatorial chemistry spaces and its applicability to focused library design. The technique was able to perform exploitation of a known scheme and at the same time explorative search for novel ligands within the framework of a given molecular core structure. It thereby represents a practical solution for compound screening in the early hit and lead finding phase of a drug discovery project.
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Iyer, Sukanya
2013-01-01
Realizing the potential of cell free systems will require development of ligand sensitive gene promoters that control gene expression in response to a ligand of interest. Here, we describe an approach to designing ligand sensitive transcriptional control in cell free systems that is based on the combination of a DNA aptamer that binds thrombin and the T7 bacteriophage promoter. Placement of the aptamer near the T7 promoter, and using a primarily single stranded template, results in up to a five-fold change in gene expression in a ligand concentration dependent manner. We further demonstrate that the sensitivity to thrombin concentration and the fold change in expression can be tuned by altering the position of the aptamer. The results described here pave the way for the use of DNA aptamers to achieve modular regulation of transcription in response to a wide variety of ligands in cell free systems. PMID:24059754
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Michino, Mayako; Chen, Jianhan; Stevens, Raymond C; Brooks, Charles L
2010-08-01
Building reliable structural models of G protein-coupled receptors (GPCRs) is a difficult task because of the paucity of suitable templates, low sequence identity, and the wide variety of ligand specificities within the superfamily. Template-based modeling is known to be the most successful method for protein structure prediction. However, refinement of homology models within 1-3 A C alpha RMSD of the native structure remains a major challenge. Here, we address this problem by developing a novel protocol (foldGPCR) for modeling the transmembrane (TM) region of GPCRs in complex with a ligand, aimed to accurately model the structural divergence between the template and target in the TM helices. The protocol is based on predicted conserved inter-residue contacts between the template and target, and exploits an all-atom implicit membrane force field. The placement of the ligand in the binding pocket is guided by biochemical data. The foldGPCR protocol is implemented by a stepwise hierarchical approach, in which the TM helical bundle and the ligand are assembled by simulated annealing trials in the first step, and the receptor-ligand complex is refined with replica exchange sampling in the second step. The protocol is applied to model the human beta(2)-adrenergic receptor (beta(2)AR) bound to carazolol, using contacts derived from the template structure of bovine rhodopsin. Comparison with the X-ray crystal structure of the beta(2)AR shows that our protocol is particularly successful in accurately capturing helix backbone irregularities and helix-helix packing interactions that distinguish rhodopsin from beta(2)AR. (c) 2010 Wiley-Liss, Inc.
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Duo, Jia; Dong, Huijin; DeSilva, Binodh; Zhang, Yan J
2013-07-01
Sample dilution and reagent pipetting are time-consuming steps in ligand-binding assays (LBAs). Traditional automation-assisted LBAs use assay-specific scripts that require labor-intensive script writing and user training. Five major script modules were developed on Tecan Freedom EVO liquid handling software to facilitate the automated sample preparation and LBA procedure: sample dilution, sample minimum required dilution, standard/QC minimum required dilution, standard/QC/sample addition, and reagent addition. The modular design of automation scripts allowed the users to assemble an automated assay with minimal script modification. The application of the template was demonstrated in three LBAs to support discovery biotherapeutic programs. The results demonstrated that the modular scripts provided the flexibility in adapting to various LBA formats and the significant time saving in script writing and scientist training. Data generated by the automated process were comparable to those by manual process while the bioanalytical productivity was significantly improved using the modular robotic scripts.
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Potent haloperidol derivatives covalently binding to the dopamine D2 receptor.
Schwalbe, Tobias; Kaindl, Jonas; Hübner, Harald; Gmeiner, Peter
2017-10-01
The dopamine D 2 receptor (D 2 R) is a common drug target for the treatment of a variety of neurological disorders including schizophrenia. Structure based design of subtype selective D 2 R antagonists requires high resolution crystal structures of the receptor and pharmacological tools promoting a better understanding of the protein-ligand interactions. Recently, we reported the development of a chemically activated dopamine derivative (FAUC150) designed to covalently bind the L94C mutant of the dopamine D 2 receptor. Using FAUC150 as a template, we elaborated the design and synthesis of irreversible analogs of the potent antipsychotic drug haloperidol forming covalent D 2 R-ligand complexes. The disulfide- and Michael acceptor-functionalized compounds showed significant receptor affinity and an irreversible binding profile in radioligand depletion experiments. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Design and Synthesis of Biaryl DNA-Encoded Libraries.
Ding, Yun; Franklin, G Joseph; DeLorey, Jennifer L; Centrella, Paolo A; Mataruse, Sibongile; Clark, Matthew A; Skinner, Steven R; Belyanskaya, Svetlana
2016-10-10
DNA-encoded library technology (ELT) is a powerful tool for the discovery of new small-molecule ligands to various protein targets. Here we report the design and synthesis of biaryl DNA-encoded libraries based on the scaffold of 5-formyl 3-iodobenzoic acid. Three reactions on DNA template, acylation, Suzuki-Miyaura coupling and reductive amination, were applied in the library synthesis. The three cycle library of 3.5 million diversity has delivered potent hits for phosphoinositide 3-kinase α (PI3Kα).
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Jin, Lihua; Lin, Shengchen; Rong, Hui
2012-03-15
Iloprost is a prostacyclin analog that has been used to treat many vascular conditions. Peroxisome proliferator-activated receptors (PPARs) are ligand-regulated transcription factors with various important biological effects such as metabolic and cardiovascular physiology. Here, we report the crystal structures of the PPAR{alpha} ligand-binding domain and PPAR{delta} ligand-binding domain bound to iloprost, thus providing unambiguous evidence for the direct interaction between iloprost and PPARs and a structural basis for the recognition of PPAR{alpha}/{delta} by this prostacyclin analog. In addition to conserved contacts for all PPAR{alpha} ligands, iloprost also initiates several specific interactions with PPARs using its unique structural groups. Structural andmore » functional studies of receptor-ligand interactions reveal strong functional correlations of the iloprost-PPAR{alpha}/{delta} interactions as well as the molecular basis of PPAR subtype selectivity toward iloprost ligand. As such, the structural mechanism may provide a more rational template for designing novel compounds targeting PPARs with more favorable pharmacologic impact based on existing iloprost drugs.« less
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Singh, Anamika; Tala, Srinivasa R; Flores, Viktor; Freeman, Katie; Haskell-Luevano, Carrie
2015-05-14
The melanocortin-3 and -4 receptors are expressed in the brain and play key roles in regulating feeding behavior, metabolism, and energy homeostasis. In the present study, incorporation of β(3)-amino acids into a melanocortin tetrapeptide template was investigated. Four linear α/β(3)-hybrid tetrapeptides were designed with the modifications at the Phe, Arg, and Trp residues in the agonist sequence Ac-His-dPhe-Arg-Trp-NH2. The most potent mouse melanocortin-4 receptor (mMC4R) agonist, Ac-His-dPhe-Arg-β(3)hTrp-NH2 (8) showed 35-fold selectivity versus the mMC3R. The study presented here has identified a new template with heterogeneous backbone for designing potent and selective melanocortin receptor ligands.
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2015-01-01
The melanocortin-3 and -4 receptors are expressed in the brain and play key roles in regulating feeding behavior, metabolism, and energy homeostasis. In the present study, incorporation of β3-amino acids into a melanocortin tetrapeptide template was investigated. Four linear α/β3-hybrid tetrapeptides were designed with the modifications at the Phe, Arg, and Trp residues in the agonist sequence Ac-His-dPhe-Arg-Trp-NH2. The most potent mouse melanocortin-4 receptor (mMC4R) agonist, Ac-His-dPhe-Arg-β3hTrp-NH2 (8) showed 35-fold selectivity versus the mMC3R. The study presented here has identified a new template with heterogeneous backbone for designing potent and selective melanocortin receptor ligands. PMID:26005535
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Mote, Nilesh R; Patel, Ketan; Shinde, Dinesh R; Gaikwad, Shahaji R; Koshti, Vijay S; Gonnade, Rajesh G; Chikkali, Samir H
2017-10-16
Self-assembly of two neutral ligands on a metal to mimic bidentate ligand coordination has been frequently encountered in the recent past, but self-assembly of an anionic ligand on a metal template alongside a neutral ligand remains an elusive target. Such a self-assembly is hampered by additional complexity, wherein a highly negatively charged anion can form intermolecular hydrogen bonding with the supramolecular motif, leaving no scope for self-assembly with neutral ligand. Presented here is the self-association of anionic ligand 3-ureidobenzoic acid (2a) and neutral ligand 1-(3-(diphenylphosphanyl)phenyl)urea (1a) on a metal template to yield metal complex [{COOC 6 H 4 NH(CO)NH 2 }{Ph 2 PC 6 H 4 NH(CO)NH 2 }PdMeDMSO] (4a). The identity of 4a was established by NMR and mass spectroscopy. Along the same lines, 3-(3-phenylureido)benzoic acid (2b) and 1-(3-(diphenylphosphanyl)phenyl)-3-phenylurea (1b) self-assemble on a metal template to produce palladium complex [{COOC 6 H 4 NH(CO)NHPh}{Ph 2 PC 6 H 4 NH(CO)NHPh}PdMePy] (5c). The existence of 5c was confirmed by Job plot, 1-2D NMR spectroscopy, deuterium labeling, IR spectroscopy, UV-vis spectroscopy, model complex synthesis, and DFT calculations. These solution and gas phase investigations authenticated the presence of intramolecular hydrogen bonding between hydrogen's of 1b and carbonyl oxygen of 2b. The generality of the supramolecular approach has been validated by preparing six complexes from four monodentate ligands, and their synthetic utility was demonstrated in ethylene polymerization. Complex 4a was found to be the most active, leading to the production of highly branched polyethylene with a molecular weight of 55700 g/mol and melting temperature of 112 °C.
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Fontana, Jake; Spillmann, Christopher; Naciri, Jawad; Ratna, Banahalli R
2014-05-09
This protocol describes a self-assembly technique to create macroscopic monolayer films composed of ligand-coated nanoparticles. The simple, robust and scalable technique efficiently functionalizes metallic nanoparticles with thiol-ligands in a miscible water/organic solvent mixture allowing for rapid grafting of thiol groups onto the gold nanoparticle surface. The hydrophobic ligands on the nanoparticles then quickly phase separate the nanoparticles from the aqueous based suspension and confine them to the air-fluid interface. This drives the ligand-capped nanoparticles to form monolayer domains at the air-fluid interface. The use of water-miscible organic solvents is important as it enables the transport of the nanoparticles from the interface onto template-free substrates. The flow is mediated by a surface tension gradient and creates macroscopic, high-density, monolayer nanoparticle-ligand films. This self-assembly technique may be generalized to include the use of particles of different compositions, size, and shape and may lead to an efficient assembly method to produce low-cost, macroscopic, high-density, monolayer nanoparticle films for wide-spread applications.
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Pharmacokinetic Steady-States Highlight Interesting Target-Mediated Disposition Properties.
Gabrielsson, Johan; Peletier, Lambertus A
2017-05-01
In this paper, we derive explicit expressions for the concentrations of ligand L, target R and ligand-target complex RL at steady state for the classical model describing target-mediated drug disposition, in the presence of a constant-rate infusion of ligand. We demonstrate that graphing the steady-state values of ligand, target and ligand-target complex, we obtain striking and often singular patterns, which yield a great deal of insight and understanding about the underlying processes. Deriving explicit expressions for the dependence of L, R and RL on the infusion rate, and displaying graphs of the relations between L, R and RL, we give qualitative and quantitive information for the experimentalist about the processes involved. Understanding target turnover is pivotal for optimising these processes when target-mediated drug disposition (TMDD) prevails. By a combination of mathematical analysis and simulations, we also show that the evolution of the three concentration profiles towards their respective steady-states can be quite complex, especially for lower infusion rates. We also show how parameter estimates obtained from iv bolus studies can be used to derive steady-state concentrations of ligand, target and complex. The latter may serve as a template for future experimental designs.
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Sernissi, Lorenzo; Trabocchi, Andrea; Scarpi, Dina; Bianchini, Francesca; Occhiato, Ernesto G
2016-02-15
4-Amino- and 5-amino-cyclopropane pipecolic acids (CPAs) with cis relative stereochemistry between the carboxylic and amino groups were used as templates to prepare cyclic peptidomimetics containing the RGD sequence as possible integrin binders. The peptidomimetic c(RGD8) built on the 5-amino-CPA displayed an inhibition activity (IC50=2.4nM) toward the αvβ3 integrin receptor (expressed in M21 human melanoma cell line) comparable to that of the most potent antagonists reported so far and it was ten times more active than the corresponding antagonist c(RGD7) derived from the isomeric 4-amino-CPA. Both compounds were also nanomolar ligands of the α5β1 integrin (expressed in human erythroleukemia cell line K562). These results suggest that the CPA-derived templates are suitable for the preparation of dual αvβ3 and α5β1 ligands to suppress integrin-mediated events as well as for targeted drug delivery in cancer therapy. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Coffinier, Yannick; Vijayalakshmi, Mookambeswaran A
2004-08-25
In this study, we attempted a limited combinatorial approach for designing affinity ligands based on mercaptoheterocyclic components. The template, divinyl sulfone structure (DVS), which was grafted on poly(ethylene vinyl alcohol) (PEVA) hollow fiber membrane, has served for the tethering of different heterocyclic compounds as pyridine, imidazole, purine and pyrimidine rings. Their ability to adsorb specifically IgG in a salt independent manner out of pure IgG solution, mixture of IgG/albumin and human plasma was demonstrated. Mercapto methyl imidazole (MMI) has shown the best adsorption of IgG in terms of binding capacity. No subclass discrimination was observed on all tested ligands except for mercapto methyl pyrimidine where the major IgG subclass adsorbed was IgG3. MMI gave an IgG binding capacity of 100 microg/cm2 of hollow fiber membrane surface area.
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Computational design of d-peptide inhibitors of hepatitis delta antigen dimerization
NASA Astrophysics Data System (ADS)
Elkin, Carl D.; Zuccola, Harmon J.; Hogle, James M.; Joseph-McCarthy, Diane
2000-11-01
Hepatitis delta virus (HDV) encodes a single polypeptide called hepatitis delta antigen (DAg). Dimerization of DAg is required for viral replication. The structure of the dimerization region, residues 12 to 60, consists of an anti-parallel coiled coil [Zuccola et al., Structure, 6 (1998) 821]. Multiple Copy Simultaneous Searches (MCSS) of the hydrophobic core region formed by the bend in the helix of one monomer of this structure were carried out for many diverse functional groups. Six critical interaction sites were identified. The Protein Data Bank was searched for backbone templates to use in the subsequent design process by matching to these sites. A 14 residue helix expected to bind to the d-isomer of the target structure was selected as the template. Over 200 000 mutant sequences of this peptide were generated based on the MCSS results. A secondary structure prediction algorithm was used to screen all sequences, and in general only those that were predicted to be highly helical were retained. Approximately 100 of these 14-mers were model built as d-peptides and docked with the l-isomer of the target monomer. Based on calculated interaction energies, predicted helicity, and intrahelical salt bridge patterns, a small number of peptides were selected as the most promising candidates. The ligand design approach presented here is the computational analogue of mirror image phage display. The results have been used to characterize the interactions responsible for formation of this model anti-parallel coiled coil and to suggest potential ligands to disrupt it.
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NASA Astrophysics Data System (ADS)
Shindel, Matthew M.
Developing processes to fabricate inorganic architectures with designer functionalities at increasingly minute length-scales is of chief concern in the fields of nanotechnology and nanoscience. This enterprise requires assembly mechanisms with the capacity to tailor both the spatial arrangement and material composition of a system's constituent building blocks. To this end, significant advances can be made by turning to biology, as the natural world has evolved the ability to generate intricate nanostructures, which can potentially be employed as templates for inorganic nanosystems. We explore this biotemplating methodology using two-dimensional streptavidin crystals, investigating the ability of the protein lattice to direct the assembly of ordered metallic nanoparticle arrays. We demonstrate that the adsorption of nanoparticles on the protein monolayer can be induced through both electrostatic and molecular recognition (ligand-receptor) interactions. Furthermore, the dynamics of adsorption can be modulated through both environmental factors (e.g. pH), and by tailoring particle surface chemistry. When the characteristic nanoparticle size is on the order of the biotemplate's unit-cell dimension, electrostatically-mediated adsorption occurs in a site-specific manner. The nanoparticles exhibit a pronounced preference for adhering to the areas between protein molecules. The two-dimensional structure of the resultant nanoparticle ensemble consequently conforms to that of the underlying protein crystal. Through theoretical calculations, simulation and experiment, we show that interparticle spacing in the templated array is influenced by the screened-coulombic repulsion between particles, and can thus be tuned by controlling ionic strength during deposition. Templating ordered nanoparticle arrays via ligand-receptor mediated adsorption, and the constrained growth of metallic nanoparticles directly on the protein lattice from ionic precursors are also examined. Overall, this work demonstrates that the streptavidin crystal system possesses unique utility for nanoscale, directed-assembly applications.
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Yamauchi, John G.; Gomez, Kimberly; Grimster, Neil; Dufouil, Mikael; Nemecz, Ákos; Fotsing, Joseph R.; Ho, Kwok-Yiu; Talley, Todd T.; Sharpless, K. Barry; Fokin, Valery V.
2012-01-01
The acetylcholine-binding proteins (AChBPs), which serve as structural surrogates for the extracellular domain of nicotinic acetylcholine receptors (nAChRs), were used as reaction templates for in situ click-chemistry reactions to generate a congeneric series of triazoles from azide and alkyne building blocks. The catalysis of in situ azide-alkyne cycloaddition reactions at a dynamic subunit interface facilitated the synthesis of potentially selective compounds for nAChRs. We investigated compound sets generated in situ with soluble AChBP templates through pharmacological characterization with α7 and α4β2 nAChRs and 5-hydroxytryptamine type 3A receptors. Analysis of activity differences between the triazole 1,5-syn- and 1,4-anti-isomers showed a preference for the 1,4-anti-triazole regioisomers among nAChRs. To improve nAChR subtype selectivity, the highest-potency building block for α7 nAChRs, i.e., 3α-azido-N-methylammonium tropane, was used for additional in situ reactions with a mutated Aplysia californica AChBP that was made to resemble the ligand-binding domain of the α7 nAChR. Fourteen of 50 possible triazole products were identified, and their corresponding tertiary analogs were synthesized. Pharmacological assays revealed that the mutated binding protein template provided enhanced selectivity of ligands through in situ reactions. Discrete trends in pharmacological profiles were evident, with most compounds emerging as α7 nAChR agonists and α4β2 nAChR antagonists. Triazoles bearing quaternary tropanes and aromatic groups were most potent for α7 nAChRs. Pharmacological characterization of the in situ reaction products established that click-chemistry synthesis with surrogate receptor templates offered novel extensions of fragment-based drug design that were applicable to multisubunit ion channels. PMID:22784805
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Wilczynski, Andrzej; Wang, Xiang S; Joseph, Christine G; Xiang, Zhimin; Bauzo, Rayna M; Scott, Joseph W; Sorensen, Nicholas B; Shaw, Amanda M; Millard, William J; Richards, Nigel G; Haskell-Luevano, Carrie
2004-04-22
Agouti-related protein (AGRP) is one of only two naturally known antagonists of G-protein-coupled receptors (GPCRs) identified to date. Specifically, AGRP antagonizes the brain melanocortin-3 and -4 receptors involved in energy homeostasis. Alpha-melanocyte stimulating hormone (alpha-MSH) is one of the known endogenous agonists for these melanocortin receptors. Insight into putative interactions between the antagonist AGRP amino acids with the melanocortin-4 receptor (MC4R) may be important for the design of unique ligands for the treatment of obesity related diseases and is currently lacking in the literature. A three-dimensional homology molecular model of the mouse MC4 receptor complex with the hAGRP(87-132) ligand docked into the receptor has been developed to identify putative antagonist ligand-receptor interactions. Key putative AGRP-MC4R interactions include the Arg111 of hAGRP(87-132) interacting in a negatively charged pocket located in a cavity formed by transmembrane spanning (TM) helices 1, 2, 3, and 7, capped by the acidic first extracellular loop (EL1) and specifically with the conserved melanocortin receptor residues mMC4R Glu92 (TM2), mMC4R Asp114 (TM3), and mMC4R Asp118 (TM3). Additionally, Phe112 and Phe113 of hAGRP(87-132) putatively interact with an aromatic hydrophobic pocket formed by the mMC4 receptor residues Phe176 (TM4), Phe193 (TM5), Phe253 (TM6), and Phe254 (TM6). To validate the AGRP-mMC4R model complex presented herein from a ligand perspective, we generated nine chimeric peptide ligands based on a modified antagonist template of the hAGRP(109-118) (Tyr-c[Asp-Arg-Phe-Phe-Asn-Ala-Phe-Dpr]-Tyr-NH(2)). In these chimeric ligands, the antagonist AGRP Arg-Phe-Phe residues were replaced by the melanocortin agonist His/D-Phe-Arg-Trp amino acids. These peptides resulted in agonist activity at the mouse melanocortin receptors (mMC1R and mMC3-5Rs). The most notable results include the identification of a novel subnanomolar melanocortin peptide template Tyr-c[Asp-His-DPhe-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) that is equipotent to alpha-MSH at the mMC1, mMC3, and mMC5 receptors but is 30-fold more potent than alpha-MSH at the mMC4R. Additionally, these studies identified a new and novel >200-fold MC4R versus MC3R selective peptide Tyr-c[Asp-D-Phe-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) template. Furthermore, when the His-DPhe-Arg-Trp sequence is used to replace the hAGRP Arg-Phe-Phe residues in the "mini"-AGRP (hAGRP87-120, C105A) template, a potent nanomolar agonist resulted at the mMC1R and MC3-5Rs.
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NASA Technical Reports Server (NTRS)
Wu, Xiaolin; Delgado, Guillermo; Krishnamurthy, Ramanarayanan; Eschenmoser, Albert
2003-01-01
Replacement of adenine by 2,6-diaminopurine-two nucleobases to be considered equivalent from an etlological point of view-strongly enhances the stability of TNA/TNA, TNA/RNA, or TNA/DNA duplexes and efficiently accelerates template-directed ligation of TNA ligands.
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Huang, Xiao-Chun; Zhang, Jie-Peng; Chen, Xiao-Ming
2004-10-20
A new facile synthetic strategy successfully leads to the isolation of two polygons of high numbers of sides constructed by simple, bent imidazolate bridging ligands and two-coordinate CuI ions upon templating of circular organic molecules, which were characterized by crystallography.
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Fu, Xiaoran; Apgar, James R.; Keating, Amy E.
2007-01-01
Computational protein design can be used to select sequences that are compatible with a fixed-backbone template. This strategy has been used in numerous instances to engineer novel proteins. However, the fixed-backbone assumption severely restricts the sequence space that is accessible via design. For challenging problems, such as the design of functional proteins, this may not be acceptable. In this paper, we present a method for introducing backbone flexibility into protein design calculations and apply it to the design of diverse helical BH3 ligands that bind to the anti-apoptotic protein Bcl-xL, a member of the Bcl-2 protein family. We demonstrate how normal mode analysis can be used to sample different BH3 backbones, and show that this leads to a larger and more diverse set of low-energy solutions than can be achieved using a native high-resolution Bcl-xL complex crystal structure as a template. We tested several of the designed solutions experimentally and found that this approach worked well when normal mode calculations were used to deform a native BH3 helix structure, but less well when they were used to deform an idealized helix. A subsequent round of design and testing identified a likely source of the problem as inadequate sampling of the helix pitch. In all, we tested seventeen designed BH3 peptide sequences, including several point mutants. Of these, eight bound well to Bcl-xL and four others showed weak but detectable binding. The successful designs showed a diversity of sequences that would have been difficult or impossible to achieve using only a fixed backbone. Thus, introducing backbone flexibility via normal mode analysis effectively broadened the set of sequences identified by computational design, and provided insight into positions important for binding Bcl-xL. PMID:17597151
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Jian, Jhih-Wei; Elumalai, Pavadai; Pitti, Thejkiran; Wu, Chih Yuan; Tsai, Keng-Chang; Chang, Jeng-Yih; Peng, Hung-Pin; Yang, An-Suei
2016-01-01
Predicting ligand binding sites (LBSs) on protein structures, which are obtained either from experimental or computational methods, is a useful first step in functional annotation or structure-based drug design for the protein structures. In this work, the structure-based machine learning algorithm ISMBLab-LIG was developed to predict LBSs on protein surfaces with input attributes derived from the three-dimensional probability density maps of interacting atoms, which were reconstructed on the query protein surfaces and were relatively insensitive to local conformational variations of the tentative ligand binding sites. The prediction accuracy of the ISMBLab-LIG predictors is comparable to that of the best LBS predictors benchmarked on several well-established testing datasets. More importantly, the ISMBLab-LIG algorithm has substantial tolerance to the prediction uncertainties of computationally derived protein structure models. As such, the method is particularly useful for predicting LBSs not only on experimental protein structures without known LBS templates in the database but also on computationally predicted model protein structures with structural uncertainties in the tentative ligand binding sites. PMID:27513851
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Hu, Xiuzhen; Dong, Qiwen; Yang, Jianyi; Zhang, Yang
2016-11-01
More than half of proteins require binding of metal and acid radical ions for their structure and function. Identification of the ion-binding locations is important for understanding the biological functions of proteins. Due to the small size and high versatility of the metal and acid radical ions, however, computational prediction of their binding sites remains difficult. We proposed a new ligand-specific approach devoted to the binding site prediction of 13 metal ions (Zn 2+ , Cu 2+ , Fe 2+ , Fe 3+ , Ca 2+ , Mg 2+ , Mn 2+ , Na + , K + ) and acid radical ion ligands (CO3 2- , NO2 - , SO4 2- , PO4 3- ) that are most frequently seen in protein databases. A sequence-based ab initio model is first trained on sequence profiles, where a modified AdaBoost algorithm is extended to balance binding and non-binding residue samples. A composite method IonCom is then developed to combine the ab initio model with multiple threading alignments for further improving the robustness of the binding site predictions. The pipeline was tested using 5-fold cross validations on a comprehensive set of 2,100 non-redundant proteins bound with 3,075 small ion ligands. Significant advantage was demonstrated compared with the state of the art ligand-binding methods including COACH and TargetS for high-accuracy ion-binding site identification. Detailed data analyses show that the major advantage of IonCom lies at the integration of complementary ab initio and template-based components. Ion-specific feature design and binding library selection also contribute to the improvement of small ion ligand binding predictions. http://zhanglab.ccmb.med.umich.edu/IonCom CONTACT: hxz@imut.edu.cn or zhng@umich.eduSupplementary information: Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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Designing interfaces of hydrogenase-nanomaterial hybrids for efficient solar conversion.
King, Paul W
2013-01-01
The direct conversion of sunlight into biofuels is an intriguing alternative to a continued reliance on fossil fuels. Natural photosynthesis has long been investigated both as a potential solution, and as a model for utilizing solar energy to drive a water-to-fuel cycle. The molecules and organizational structure provide a template to inspire the design of efficient molecular systems for photocatalysis. A clear design strategy is the coordination of molecular interactions that match kinetic rates and energetic levels to control the direction and flow of energy from light harvesting to catalysis. Energy transduction and electron-transfer reactions occur through interfaces formed between complexes of donor-acceptor molecules. Although the structures of several of the key biological complexes have been solved, detailed descriptions of many electron-transfer complexes are lacking, which presents a challenge to designing and engineering biomolecular systems for solar conversion. Alternatively, it is possible to couple the catalytic power of biological enzymes to light harvesting by semiconductor nanomaterials. In these molecules, surface chemistry and structure can be designed using ligands. The passivation effect of the ligand can also dramatically affect the photophysical properties of the semiconductor, and energetics of external charge-transfer. The length, degree of bond saturation (aromaticity), and solvent exposed functional groups of ligands can be manipulated to further tune the interface to control molecular assembly, and complex stability in photocatalytic hybrids. The results of this research show how ligand selection is critical to designing molecular interfaces that promote efficient self-assembly, charge-transfer and photocatalysis. This article is part of a Special Issue entitled: Metals in Bioenergetics and Biomimetics Systems. Copyright © 2013 Elsevier B.V. All rights reserved.
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ProBiS-ligands: a web server for prediction of ligands by examination of protein binding sites.
Konc, Janez; Janežič, Dušanka
2014-07-01
The ProBiS-ligands web server predicts binding of ligands to a protein structure. Starting with a protein structure or binding site, ProBiS-ligands first identifies template proteins in the Protein Data Bank that share similar binding sites. Based on the superimpositions of the query protein and the similar binding sites found, the server then transposes the ligand structures from those sites to the query protein. Such ligand prediction supports many activities, e.g. drug repurposing. The ProBiS-ligands web server, an extension of the ProBiS web server, is open and free to all users at http://probis.cmm.ki.si/ligands. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.
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@TOME-2: a new pipeline for comparative modeling of protein-ligand complexes.
Pons, Jean-Luc; Labesse, Gilles
2009-07-01
@TOME 2.0 is new web pipeline dedicated to protein structure modeling and small ligand docking based on comparative analyses. @TOME 2.0 allows fold recognition, template selection, structural alignment editing, structure comparisons, 3D-model building and evaluation. These tasks are routinely used in sequence analyses for structure prediction. In our pipeline the necessary software is efficiently interconnected in an original manner to accelerate all the processes. Furthermore, we have also connected comparative docking of small ligands that is performed using protein-protein superposition. The input is a simple protein sequence in one-letter code with no comment. The resulting 3D model, protein-ligand complexes and structural alignments can be visualized through dedicated Web interfaces or can be downloaded for further studies. These original features will aid in the functional annotation of proteins and the selection of templates for molecular modeling and virtual screening. Several examples are described to highlight some of the new functionalities provided by this pipeline. The server and its documentation are freely available at http://abcis.cbs.cnrs.fr/AT2/
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@TOME-2: a new pipeline for comparative modeling of protein–ligand complexes
Pons, Jean-Luc; Labesse, Gilles
2009-01-01
@TOME 2.0 is new web pipeline dedicated to protein structure modeling and small ligand docking based on comparative analyses. @TOME 2.0 allows fold recognition, template selection, structural alignment editing, structure comparisons, 3D-model building and evaluation. These tasks are routinely used in sequence analyses for structure prediction. In our pipeline the necessary software is efficiently interconnected in an original manner to accelerate all the processes. Furthermore, we have also connected comparative docking of small ligands that is performed using protein–protein superposition. The input is a simple protein sequence in one-letter code with no comment. The resulting 3D model, protein–ligand complexes and structural alignments can be visualized through dedicated Web interfaces or can be downloaded for further studies. These original features will aid in the functional annotation of proteins and the selection of templates for molecular modeling and virtual screening. Several examples are described to highlight some of the new functionalities provided by this pipeline. The server and its documentation are freely available at http://abcis.cbs.cnrs.fr/AT2/ PMID:19443448
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NASA Astrophysics Data System (ADS)
Masih, Iffat; Fahmi, Nighat
2011-09-01
A new series of Pd(II) macrocyclic complexes have been synthesized by template condensation of bis(benzil)4-chloro 1,2-phenylenediamine (ML 1) and bis(benzil)4-fluro 1,2-phenylenediamine (ML 2) respectively, with appropriate diamine i.e. 1,2-phenylenediamine, 4-chloro 1,2-phenylenediamine and 4-fluro 1,2-phenylenediamine in the presence of PdCl 2 to form complexes of the type [Pd(C 40H 26N 4ClF)]Cl 2, [Pd(C 40H 27N 4X)]Cl 2 and [Pd(C 40H 26N 4X 2)]Cl 2, where X = Cl, F. The complexes have been characterized with the help of elemental analysis, IR, 1H NMR, electronic spectra, conductance measurement, magnetic susceptibility, cyclic voltammetry and X-ray powder diffraction studies. On the basis of these studies a square planar geometry has been proposed around the metal ion. The newly synthesized ligands and their complexes have been screened for antimicrobial and pesticidal activities. The results obtained from bioassays indicate that this class of compounds can be utilized for the design of new substance with pesticidal activity and promising antimicrobial activity.
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Singh, Anamika; Wilczynski, Andrzej; Holder, Jerry R.; Witek, Rachel M.; Dirain, Marvin L.; Xiang, Zhimin; Edison, Arthur S.; Haskell-Luevano, Carrie
2011-01-01
Using a solid-phase synthetic approach, a bioactive reverse turn heterocyclic was incorporated into a cyclic peptide template to probe melanocortin receptor potency and ligand structural conformations. The five melanocortin receptor isoforms (MC1R-MC5R) are G-protein coupled receptors (GPCRs) that are regulated by endogenous agonists and antagonists. This pathway is involved in pigmentation, weight, and energy homeostasis. Herein, we report novel analogues of the chimeric AGRP-melanocortin peptide template integrated with a small molecule moiety to probe the structural and functional consequences of the core His-Phe-Arg-Trp peptide domain using a reverse-turn heterocycle. A series of six compounds are reported that result in inactive to full agonists with nM potency. Biophysical structural analysis [2D 1H NMR and computer-assisted molecular modeling (CAMM)] were performed on selected analogues, resulting in the identification that these peptide-small molecule hybrids possessed increased flexibility and fewer discrete conformational families as compared to the reference peptide and result in a novel template for further structure-function studies. PMID:21306168
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Singh, Anamika; Dirain, Marvin; Witek, Rachel; Rocca, James R.; Edison, Arthur S; Haskell-Luevano, Carrie
2013-01-01
The melanocortin-3 (MC3) and melanocortin-4 (MC4) receptors regulate energy homeostasis, food intake, and associated physiological conditions. The MC4R has been studied extensively. Less is known about specific physiological roles of the MC3R. A major obstacle to this lack of knowledge is attributed to a limited number of identified MC3R selective ligands. We previously reported a spatial scanning approach of a 10-membered thioether-heterocycle ring incorporated into a chimeric peptide template that identified a lead nM MC4R ligand. Based upon those results, 17 compounds were designed and synthesized that focused upon modification in the pharmacophore domain. Notable results include the identification of a 0.13 nM potent 5800-fold mMC3R selective antagonist/slight partial agonist versus a 760 nM mMC4R full agonist (ligand 11). Biophysical experiments (2D 1H NMR and computer assisted molecular modeling) of this ligand resulted in the identification of an inverse γ-turn secondary structure in the ligand pharmacophore domain. PMID:23432160
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Murrray, George M.; Uy, O. Manuel
The purpose of this research is to develop polymeric extractants for the selective complexation of uranyl ions (and subsequently other actinyl and actinide ions) from aqueous solutions. Selectivity for a specific actinide ion is obtained by providing the polymers with cavities lined with complexing ligands so arranged as to match the charge, coordination number, coordination geometry, and size of the actinide ion. These cavity-containing polymers are produced by using a specific actinide ion (or surrogate) as a template around which monomeric complexing ligands are polymerized. The polymers provide useful sequestering agents for removing actinide ions from wastes and will formmore » the basis for a variety of analytical techniques for actinide determination.« less
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In silico designed nanoMIP based optical sensor for endotoxins monitoring.
Abdin, M J; Altintas, Z; Tothill, I E
2015-05-15
Molecular modelling was used to select specific monomers suitable for the design of molecularly imprinted polymers (MIPs) with high affinity towards endotoxins. MIPs were synthesised using solid-phase photopolymerisation with endotoxins from Escherichia coli 0111:B4 as the template. This technique also allowed the endotoxin template to be reused successfully. Particle size of ~190-220 nm was achieved with low polydispersity index, which confirms the quality of the produced MIPs. For the development of the optical sensor, SPR-2 biosensor system was used by functionalising the gold sensor chip with the MIP nanoparticles using EDC/NHS coupling procedure. The affinity based-endotoxin assay can detect endotoxins in the concentration range of 15.6-500 ng mL(-1). MIP surfaces were regenerated showing stability of the method for subsequent analysis and dissociation constants were calculated as 3.24-5.24×10(-8) M. The developed SPR sensor with the novel endotoxins nanoMIP showed the potential of the technology for endotoxins capture, detection and risk management and also the importance of computational modelling to design the artificial affinity ligands. Copyright © 2014 Elsevier B.V. All rights reserved.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Fryxell, Glen E.; Mattigod, Shas V.; Lin, Yuehe
2007-07-01
Water, and water quality, are issues of critical importance to the future of humankind. The Earth’s water supplies have been contaminated by a wide variety of industrial, military and natural sources. The need exists for an efficient separation technology to remove heavy metal and radionuclide contamination from water. Surfactant templated synthesis of mesoporous ceramics provides a versatile foundation upon which to build high efficiency environmental sorbents. These nanoporous ceramics condense a huge amount of surface area into a very small volume. These mesoporous architectures can be subsequently functionalized through molecular self-assembly. These functional mesoporous materials offer significant capabilities in termsmore » of removal of heavy metals and radionuclides from a variety of liquid media, including groundwater, contaminated oils and contaminated chemical weapons. They are highly efficient sorbents, whose rigid, open pore structure allows for rapid, efficient sorption kinetics. Their interfacial chemistry can be fine-tuned to selectively sequester a specific target species, such as heavy metals, tetrahedral oxometallate anions and radionuclides. This manuscript provides a review of the design, synthesis and performance of the sorbent materials. The role that ligand posture plays in the chemistry of these interfacial ligand fields is discussed.« less
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Template-Free Mesoporous Electrochromic Films on Flexible Substrates from Tungsten Oxide Nanorods
Heo, Sungyeon; Kim, Jongwook; Ong, Gary K.; ...
2017-08-08
Low-temperature processed mesoporous nanocrystal thin films are platforms for fabricating functional composite thin films on flexible substrates. Using a random arrangement of anisotropic nanocrystals can be a facile solution to generate pores without templates. However, the tendency for anisotropic particles to spontaneously assemble into a compact structure must be overcome. Here in this paper, we present a method to achieve random networking of nanorods during solution phase deposition by switching their ligand-stabilized colloidal nature into a charge-stabilized nature by a ligand-stripping chemistry. Ligand-stripped tungsten suboxide (WO 2.72) nanorods result in uniform mesoporous thin films owing to repulsive electrostatic forces preventingmore » nanorods from densely packing. Porosity and pore size distribution of thin films are controlled by changing the aspect ratio of the nanorods. This template-free mesoporous structure, achieved without annealing, provides a framework for introducing guest components, therefore enabling our fabrication of inorganic nanocomposite electrochromic films on flexible substrates. Following infilling of niobium polyoxometalate clusters into pores and successive chemical condensation, a WO x–NbO x composite film is produced that selectively controls visible and near-infrared light transmittance without any annealing required. The composite shows rapid switching kinetics and can be stably cycled between optical states over 2000 times. This simple strategy of using anisotropic nanocrystals gives insight into mesoporous thin film fabrication with broader applications for flexible devices.« less
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Template-Free Mesoporous Electrochromic Films on Flexible Substrates from Tungsten Oxide Nanorods
DOE Office of Scientific and Technical Information (OSTI.GOV)
Heo, Sungyeon; Kim, Jongwook; Ong, Gary K.
Low-temperature processed mesoporous nanocrystal thin films are platforms for fabricating functional composite thin films on flexible substrates. Using a random arrangement of anisotropic nanocrystals can be a facile solution to generate pores without templates. However, the tendency for anisotropic particles to spontaneously assemble into a compact structure must be overcome. Here in this paper, we present a method to achieve random networking of nanorods during solution phase deposition by switching their ligand-stabilized colloidal nature into a charge-stabilized nature by a ligand-stripping chemistry. Ligand-stripped tungsten suboxide (WO 2.72) nanorods result in uniform mesoporous thin films owing to repulsive electrostatic forces preventingmore » nanorods from densely packing. Porosity and pore size distribution of thin films are controlled by changing the aspect ratio of the nanorods. This template-free mesoporous structure, achieved without annealing, provides a framework for introducing guest components, therefore enabling our fabrication of inorganic nanocomposite electrochromic films on flexible substrates. Following infilling of niobium polyoxometalate clusters into pores and successive chemical condensation, a WO x–NbO x composite film is produced that selectively controls visible and near-infrared light transmittance without any annealing required. The composite shows rapid switching kinetics and can be stably cycled between optical states over 2000 times. This simple strategy of using anisotropic nanocrystals gives insight into mesoporous thin film fabrication with broader applications for flexible devices.« less
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2015-01-01
The melanocortin-3 (MC3R) and melanocortin-4 (MC4R) receptors are expressed in the brain and are implicated in the regulation of food intake and energy homeostasis. The endogenous agonist ligands for these receptors (α-, β-, γ-MSH and ACTH) are linear peptides with limited receptor subtype selectivity and metabolic stability, thus minimizing their use as probes to characterize the overlapping pharmacological and physiological functions of the melanocortin receptor subtypes. In the present study, an engineered template, in which the peptide backbone was modified by a heterocyclic reverse turn mimetic at the Trp7 residue, was synthesized using solid phase peptide synthesis and characterized by a β-galactosidase cAMP based reporter gene assay. The functional assay identified a ∼5 nM mouse MC4R agonist (AST3-88) with more than 50-fold selectivity over the mMC3R. Biophysical studies (2D 1H NMR spectroscopy and molecular dynamics) of AST3-88 identified a type VIII β-turn secondary structure spanning the pharmacophore domain stabilized by the intramolecular interactions between the side chains of the His and Trp residues. Enzymatic studies of AST3-88 revealed enhanced stability of AST3-88 over the α-MSH endogenous peptide in rat serum. Upon central administration of AST3-88 into rats, a decreased food intake response was observed. This is the first study to probe the in vivo physiological activity of this engineered peptide-heterocycle template. These findings advance the present knowledge of pharmacophore design for potent, selective, and metabolically stable melanocortin ligands. PMID:25141170
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Doubling the Size of the Glucocorticoid Receptor Ligand Binding Pocket by Deacylcortivazol
DOE Office of Scientific and Technical Information (OSTI.GOV)
Suino-Powell, Kelly; Xu, Yong; Zhang, Chenghai
A common feature of nuclear receptor ligand binding domains (LBD) is a helical sandwich fold that nests a ligand binding pocket within the bottom half of the domain. Here we report that the ligand pocket of glucocorticoid receptor (GR) can be continuously extended into the top half of the LBD by binding to deacylcortivazol (DAC), an extremely potent glucocorticoid. It has been puzzling for decades why DAC, which contains a phenylpyrazole replacement at the conserved 3-ketone of steroid hormones that are normally required for activation of their cognate receptors, is a potent GR activator. The crystal structure of the GRmore » LBD bound to DAC and the fourth LXXLL motif of steroid receptor coactivator 1 reveals that the GR ligand binding pocket is expanded to a size of 1,070 {angstrom}{sup 3}, effectively doubling the size of the GR dexamethasone-binding pocket of 540 {angstrom}{sup 3} and yet leaving the structure of the coactivator binding site intact. DAC occupies only {approx}50% of the space of the pocket but makes intricate interactions with the receptor around the phenylpyrazole group that accounts for the high-affinity binding of DAC. The dramatic expansion of the DAC-binding pocket thus highlights the conformational adaptability of GR to ligand binding. The new structure also allows docking of various nonsteroidal ligands that cannot be fitted into the previous structures, thus providing a new rational template for drug discovery of steroidal and nonsteroidal glucocorticoids that can be specifically designed to reach the unoccupied space of the expanded pocket.« less
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NASA Astrophysics Data System (ADS)
Cheng, Rui; Xu, Jing; Zhang, Xiafei; Shi, Zhilu; Zhang, Qi; Jin, Yan
2017-03-01
Herein, the conformational switch of G-rich oligonucleotide (GDNA) demonstrated the obvious functional switch of GDNA which was found to significantly affect the fluorescence of the in-situ synthesized DNA/silver nanocluster (DNA-AgNC) in homogeneous solution. We envisioned that the allosteric interaction between GDNA and DNA-AgNC would be possible to be used for screening telomere-binding ligands. A unimolecular probe (12C5TG) is ingeniously designed consisting of three contiguous DNA elements: G-rich telomeric DNA (GDNA) as molecular recognition sequence, T-rich DNA as linker and C-rich DNA as template of DNA-AgNC. The quantum yield and stability of 12C5TG-AgNC is greatly improved because the nearby deoxyguanosines tended to protect DNA/AgNC against oxidation. However, in the presence of ligands, the formation of G-quadruplex obviously quenched the fluorescence of DNA-AgNC. By taking full advantage of intramolecular allosteric effect, telomere-binding ligands were selectively and label-free screened by using deoxyguanines and G-quadruplex as natural fluorescence enhancer and quencher of DNA-AgNC respectively. Therefore, the functional switching of G-rich structure offers a cost-effective, facile and reliable way to screen drugs, which holds a great potential in bioanalysis as well.
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General method for the synthesis of hierarchical nanocrystal-based mesoporous materials.
Rauda, Iris E; Buonsanti, Raffaella; Saldarriaga-Lopez, Laura C; Benjauthrit, Kanokraj; Schelhas, Laura T; Stefik, Morgan; Augustyn, Veronica; Ko, Jesse; Dunn, Bruce; Wiesner, Ulrich; Milliron, Delia J; Tolbert, Sarah H
2012-07-24
Block copolymer templating of inorganic materials is a robust method for the production of nanoporous materials. The method is limited, however, by the fact that the molecular inorganic precursors commonly used generally form amorphous porous materials that often cannot be crystallized with retention of porosity. To overcome this issue, here we present a general method for the production of templated mesoporous materials from preformed nanocrystal building blocks. The work takes advantage of recent synthetic advances that allow organic ligands to be stripped off of the surface of nanocrystals to produce soluble, charge-stabilized colloids. Nanocrystals then undergo evaporation-induced co-assembly with amphiphilic diblock copolymers to form a nanostructured inorganic/organic composite. Thermal degradation of the polymer template results in nanocrystal-based mesoporous materials. Here, we show that this method can be applied to nanocrystals with a broad range of compositions and sizes, and that assembly of nanocrystals can be carried out using a broad family of polymer templates. The resultant materials show disordered but homogeneous mesoporosity that can be tuned through the choice of template. The materials also show significant microporosity, formed by the agglomerated nanocrystals, and this porosity can be tuned by the nanocrystal size. We demonstrate through careful selection of the synthetic components that specifically designed nanostructured materials can be constructed. Because of the combination of open and interconnected porosity, high surface area, and compositional tunability, these materials are likely to find uses in a broad range of applications. For example, enhanced charge storage kinetics in nanoporous Mn(3)O(4) is demonstrated here.
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Hierarchical Metal–Organic Framework Hybrids: Perturbation-Assisted Nanofusion Synthesis
Yue, Yanfeng; Fulvio, Pasquale F.; Dai, Sheng
2015-12-04
Metal–organic frameworks (MOFs) represent a new family of microporous materials; however, microporous–mesoporous hierarchical MOF materials have been less investigated because of the lack of simple, reliable methods to introduce mesopores to the crystalline microporous particles. State-of-the-art MOF hierarchical materials have been prepared by ligand extension methods or by using a template, resulting in intrinsic mesopores of longer ligands or replicated pores from template agents, respectively. However, mesoporous MOF materials obtained through ligand extension often collapse in the absence of guest molecules, which dramatically reduces the size of the pore aperture. Although the template-directed strategy allows for the preparation of hierarchicalmore » materials with larger mesopores, the latter requires a template removal step, which may result in the collapse of the implemented mesopores. Recently, a general template-free synthesis of hierarchical microporous crystalline frameworks, such as MOFs and Prussian blue analogues (PBAs), has been reported. Our new method is based on the kinetically controlled precipitation (perturbation), with simultaneous condensation and redissolution of polymorphic nanocrystallites in the mother liquor. This method further eliminates the use of extended organic ligands and the micropores do not collapse upon removal of trapped guest solvent molecules, thus yielding hierarchical MOF materials with intriguing porosity in the gram scale. The hierarchical MOF materials prepared in this way exhibited exceptional properties when tested for the adsorption of large organic dyes over their corresponding microporous frameworks, due to the enhanced pore accessibility and electrolyte diffusion within the mesopores. As for PBAs, the pore size distribution of these materials can be tailored by changing the metals substituting Fe cations in the PB lattice. For these, the textural mesopores increased from approximately 10 nm for Cu analogue (mesoCuHCF), to 16 nm in Co substituted compound (mesoCoHCF), and to as large as 30 nm for the Ni derivative (mesoNiHCF). And while bulk PB and analogues have a higher capacitance than hierarchical analogues for Na-batteries, the increased accessibility to the microporous channels of PBAs allow for faster intercalated ion exchange and diffusion than in bulk PBA crystals. Therefore, hierarchical PBAs are promising candidates for electrodes in future electrochemical energy storage devices with faster charge–discharge rates than batteries, namely pseudocapacitors. Finally, this new synthetic method opens the possibility to prepare hierarchical materials having bimodal distribution of mesopores, and to tailor the structural properties of MOFs for different applications, including contrasting agents for MRI, and drug delivery.« less
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Interference between Triplex and Protein Binding to Distal Sites on Supercoiled DNA.
Noy, Agnes; Maxwell, Anthony; Harris, Sarah A
2017-02-07
We have explored the interdependence of the binding of a DNA triplex and a repressor protein to distal recognition sites on supercoiled DNA minicircles using MD simulations. We observe that the interaction between the two ligands through their influence on their DNA template is determined by a subtle interplay of DNA mechanics and electrostatics, that the changes in flexibility induced by ligand binding play an important role and that supercoiling can instigate additional ligand-DNA contacts that would not be possible in simple linear DNA sequences. Copyright © 2017. Published by Elsevier Inc.
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Gadhe, Changdev G; Kim, Mi-hyun
2015-02-01
CC chemokine receptor 4 (CCR4), a G protein-coupled receptor (GPCR), plays a vital role in the progression of asthma, T-cell lymphoma, inflammation, and Alzheimer's disease. To date, the structure of CCR4 has not been determined. Therefore, the nature of the interactions between inhibitors and CCR4 is not well known. In this study, we used CCR5 as a template to model the structure of CCR4. Docking studies were performed for four naphthalene-sulphonamide derivatives and crucial ligand-protein interactions were analysed. Molecular dynamics (MD) simulations of these complexes (100 ns each) were carried out to gain insights into the interactions between ligands and CCR4. MD simulations revealed that the residues identified by the docking were displaced and new residues were inserted near the ligands. Results of a principal component analysis (PCA) suggested that CCR4 unfolds at the extracellular site surrounding the ligands. Our simulations identified crucial residues involved in CCR4 antagonism, which were supported by previous mutational studies. Additionally, we identified Ser3.29, Leu3.33, Ser5.39, Phe6.47, Ile7.35, Thr7.38, Thr7.40, and Ala7.42 as residues that play crucial roles in CCR4 antagonism. Mutational studies will help elucidate the significance of these residues in CCR4 antagonism. An understanding of ligand-CCR4 interactions might aid in the design of novel CCR4 inhibitors.
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Thermally Stable Gold Nanoparticles with a Crosslinked Diblock Copolymer Shell
NASA Astrophysics Data System (ADS)
Jang, Se Gyu; Khan, Anzar; Hawker, Craig J.; Kramer, Edward J.
2010-03-01
The use of polymer-coated Au nanoparticles prepared using oligomeric- or polymeric-ligands tethered by Au-S bonds for incorporation into block copolymer templates under thermal processing has been limited due to dissociation of the Au-S bond at T > 100^oC where compromises their colloidal stability. We report a simple route to prepare sub-5nm gold nanoparticles with a thermally stable polymeric shell. An end-functional thiol ligand consisting of poly(styrene-b-1,2&3,4-isoprene-SH) is synthesized by anionic polymerization. After a standard thiol ligand synthesis of Au nanoparticles, the inner PI block is cross-linked through reaction with 1,1,3,3-tetramethyldisiloxane. Gold nanoparticles with the cross-linked shell are stable in organic solvents at 160^oC as well as in block copolymer films of PS-b-P2VP annealed in vacuum at 170^oC for several days. These nanoparticles can be designed to strongly segregate to the PS-P2VP interface resulting in very large Au nanoparticle volume fractions φp without macrophase separation as well as transitions between lamellar and bicontinuous morphologies as φp increases.
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Morini, Gabriella; Bassoli, Angela; Temussi, Piero A
2005-08-25
The sweet taste receptor, a heterodimeric G protein coupled receptor (GPCR) protein, formed by the T1R2 and T1R3 subunits, recognizes several sweet compounds including carbohydrates, amino acids, peptides, proteins, and synthetic sweeteners. Its similarity with the metabotropic glutamate mGluR1 receptor allowed us to build homology models. All possible dimers formed by combinations of the human T1R2 and T1R3 subunits, modeled on the A (closed) or B (open) chains of the extracellular ligand binding domain of the mGluR1 template, yield four ligand binding sites for low-molecular-weight sweeteners. These sites were probed by docking a set of molecules representative of all classes of sweet compounds and calculating the free energy of ligand binding. These sites are not easily accessible to sweet proteins, but docking experiments in silico showed that sweet proteins can bind to a secondary site without entering the deep cleft. Our models account for many experimental observations on the tastes of sweeteners, including sweetness synergy, and can help to design new sweeteners.
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Nguyen, Phuong-Diem; Cong, Vu Thanh; Baek, Changyoon; Min, Junhong
2017-03-15
This study introduces the double-ligands stabilizing gold nanoclusters and the fabrication of gold nanocluster/graphene nanocomplex as a "turn-on" fluorescent probe for the detection of cancer-related enzyme matrix metalloproteinase-9. A facile, one-step approach was developed for the synthesis of fluorescent gold nanoclusters using peptides and mercaptoundecanoic acid as co-templating ligands. The peptide was designed to possess a metalloproteinase-9 cleavage site and to act not only as a stabilizer but also as a targeting ligand for the enzyme detection. The prepared gold nanoclusters show an intense red fluorescence with a broad adsorption spectrum. In the presence of the enzyme, due to the excellent quenching properties and the negligible background of graphene oxide, the developed peptide-gold nanocluster/graphene nanocomplex yielded an intense "turn-on" fluorescent response, which strongly correlated with the enzyme concentration. The limit of detection of the nanocomplex was 0.15nM. The sensor was successfully applied for "turn-on" detection of metalloproteinase-9 secreted from human breast adenocarcinoma MCF-7 cells with high sensitivity, selectivity, significant improvement in terms of detection time and simplicity. Copyright © 2015 Elsevier B.V. All rights reserved.
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IADE: a system for intelligent automatic design of bioisosteric analogs
NASA Astrophysics Data System (ADS)
Ertl, Peter; Lewis, Richard
2012-11-01
IADE, a software system supporting molecular modellers through the automatic design of non-classical bioisosteric analogs, scaffold hopping and fragment growing, is presented. The program combines sophisticated cheminformatics functionalities for constructing novel analogs and filtering them based on their drug-likeness and synthetic accessibility using automatic structure-based design capabilities: the best candidates are selected according to their similarity to the template ligand and to their interactions with the protein binding site. IADE works in an iterative manner, improving the fitness of designed molecules in every generation until structures with optimal properties are identified. The program frees molecular modellers from routine, repetitive tasks, allowing them to focus on analysis and evaluation of the automatically designed analogs, considerably enhancing their work efficiency as well as the area of chemical space that can be covered. The performance of IADE is illustrated through a case study of the design of a nonclassical bioisosteric analog of a farnesyltransferase inhibitor—an analog that has won a recent "Design a Molecule" competition.
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IADE: a system for intelligent automatic design of bioisosteric analogs.
Ertl, Peter; Lewis, Richard
2012-11-01
IADE, a software system supporting molecular modellers through the automatic design of non-classical bioisosteric analogs, scaffold hopping and fragment growing, is presented. The program combines sophisticated cheminformatics functionalities for constructing novel analogs and filtering them based on their drug-likeness and synthetic accessibility using automatic structure-based design capabilities: the best candidates are selected according to their similarity to the template ligand and to their interactions with the protein binding site. IADE works in an iterative manner, improving the fitness of designed molecules in every generation until structures with optimal properties are identified. The program frees molecular modellers from routine, repetitive tasks, allowing them to focus on analysis and evaluation of the automatically designed analogs, considerably enhancing their work efficiency as well as the area of chemical space that can be covered. The performance of IADE is illustrated through a case study of the design of a nonclassical bioisosteric analog of a farnesyltransferase inhibitor--an analog that has won a recent "Design a Molecule" competition.
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Assessment and Challenges of Ligand Docking into Comparative Models of G-Protein Coupled Receptors
Frimurer, Thomas M.; Meiler, Jens
2013-01-01
The rapidly increasing number of high-resolution X-ray structures of G-protein coupled receptors (GPCRs) creates a unique opportunity to employ comparative modeling and docking to provide valuable insight into the function and ligand binding determinants of novel receptors, to assist in virtual screening and to design and optimize drug candidates. However, low sequence identity between receptors, conformational flexibility, and chemical diversity of ligands present an enormous challenge to molecular modeling approaches. It is our hypothesis that rapid Monte-Carlo sampling of protein backbone and side-chain conformational space with Rosetta can be leveraged to meet this challenge. This study performs unbiased comparative modeling and docking methodologies using 14 distinct high-resolution GPCRs and proposes knowledge-based filtering methods for improvement of sampling performance and identification of correct ligand-receptor interactions. On average, top ranked receptor models built on template structures over 50% sequence identity are within 2.9 Å of the experimental structure, with an average root mean square deviation (RMSD) of 2.2 Å for the transmembrane region and 5 Å for the second extracellular loop. Furthermore, these models are consistently correlated with low Rosetta energy score. To predict their binding modes, ligand conformers of the 14 ligands co-crystalized with the GPCRs were docked against the top ranked comparative models. In contrast to the comparative models themselves, however, it remains difficult to unambiguously identify correct binding modes by score alone. On average, sampling performance was improved by 103 fold over random using knowledge-based and energy-based filters. In assessing the applicability of experimental constraints, we found that sampling performance is increased by one order of magnitude for every 10 residues known to contact the ligand. Additionally, in the case of DOR, knowledge of a single specific ligand-protein contact improved sampling efficiency 7 fold. These findings offer specific guidelines which may lead to increased success in determining receptor-ligand complexes. PMID:23844000
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Aucagne, Vincent; Berna, José; Crowley, James D; Goldup, Stephen M; Hänni, Kevin D; Leigh, David A; Lusby, Paul J; Ronaldson, Vicki E; Slawin, Alexandra M Z; Viterisi, Aurélien; Walker, D Barney
2007-10-03
A synthetic approach to rotaxane architectures is described in which metal atoms catalyze covalent bond formation while simultaneously acting as the template for the assembly of the mechanically interlocked structure. This "active-metal" template strategy is exemplified using the Huisgen-Meldal-Fokin Cu(I)-catalyzed 1,3-cycloaddition of azides with terminal alkynes (the CuAAC "click" reaction). Coordination of Cu(I) to an endotopic pyridine-containing macrocycle allows the alkyne and azide to bind to metal atoms in such a way that the metal-mediated bond-forming reaction takes place through the cavity of the macrocycle--or macrocycles--forming a rotaxane. A variety of mono- and bidentate macrocyclic ligands are demonstrated to form [2]rotaxanes in this way, and by adding pyridine, the metal can turn over during the reaction, giving a catalytic active-metal template assembly process. Both the stoichiometric and catalytic versions of the reaction were also used to synthesize more complex two-station molecular shuttles. The dynamics of the translocation of the macrocycle by ligand exchange in these two-station shuttles could be controlled by coordination to different metal ions (rapid shuttling is observed with Cu(I), slow shuttling with Pd(II)). Under active-metal template reaction conditions that feature a high macrocycle:copper ratio, [3]rotaxanes (two macrocycles on a thread containing a single triazole ring) are also produced during the reaction. The latter observation shows that under these conditions the mechanism of the Cu(I)-catalyzed terminal alkyne-azide cycloaddition involves a reactive intermediate that features at least two metal ions.
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2016-01-01
Abstract Molecular recognition by protein mostly occurs in a local region on the protein surface. Thus, an efficient computational method for accurate characterization of protein local structural conservation is necessary to better understand biology and drug design. We present a novel local structure alignment tool, G‐LoSA. G‐LoSA aligns protein local structures in a sequence order independent way and provides a GA‐score, a chemical feature‐based and size‐independent structure similarity score. Our benchmark validation shows the robust performance of G‐LoSA to the local structures of diverse sizes and characteristics, demonstrating its universal applicability to local structure‐centric comparative biology studies. In particular, G‐LoSA is highly effective in detecting conserved local regions on the entire surface of a given protein. In addition, the applications of G‐LoSA to identifying template ligands and predicting ligand and protein binding sites illustrate its strong potential for computer‐aided drug design. We hope that G‐LoSA can be a useful computational method for exploring interesting biological problems through large‐scale comparison of protein local structures and facilitating drug discovery research and development. G‐LoSA is freely available to academic users at http://im.compbio.ku.edu/GLoSA/. PMID:26813336
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Lee, Hui Sun; Im, Wonpil
2016-04-01
Molecular recognition by protein mostly occurs in a local region on the protein surface. Thus, an efficient computational method for accurate characterization of protein local structural conservation is necessary to better understand biology and drug design. We present a novel local structure alignment tool, G-LoSA. G-LoSA aligns protein local structures in a sequence order independent way and provides a GA-score, a chemical feature-based and size-independent structure similarity score. Our benchmark validation shows the robust performance of G-LoSA to the local structures of diverse sizes and characteristics, demonstrating its universal applicability to local structure-centric comparative biology studies. In particular, G-LoSA is highly effective in detecting conserved local regions on the entire surface of a given protein. In addition, the applications of G-LoSA to identifying template ligands and predicting ligand and protein binding sites illustrate its strong potential for computer-aided drug design. We hope that G-LoSA can be a useful computational method for exploring interesting biological problems through large-scale comparison of protein local structures and facilitating drug discovery research and development. G-LoSA is freely available to academic users at http://im.compbio.ku.edu/GLoSA/. © 2016 The Protein Society.
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NASA Astrophysics Data System (ADS)
Panda, Deepanjan; Saha, Puja; Das, Tania; Dash, Jyotirmayee
2017-07-01
The development of small molecules is essential to modulate the cellular functions of biological targets in living system. Target Guided Synthesis (TGS) approaches have been used for the identification of potent small molecules for biological targets. We herein demonstrate an innovative example of TGS using DNA nano-templates that promote Huisgen cycloaddition from an array of azide and alkyne fragments. A G-quadruplex and a control duplex DNA nano-template have been prepared by assembling the DNA structures on gold-coated magnetic nanoparticles. The DNA nano-templates facilitate the regioselective formation of 1,4-substituted triazole products, which are easily isolated by magnetic decantation. The G-quadruplex nano-template can be easily recovered and reused for five reaction cycles. The major triazole product, generated by the G-quadruplex inhibits c-MYC expression by directly targeting the c-MYC promoter G-quadruplex. This work highlights that the nano-TGS approach may serve as a valuable strategy to generate target-selective ligands for drug discovery.
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The Self-Assembly of Nanogold for Optical Metamaterials
NASA Astrophysics Data System (ADS)
Nidetz, Robert A.
2011-12-01
Optical metamaterials are an emerging field that enables manipulation of light like never before. Producing optical metamaterials requires sub-wavelength building blocks. The focus here was to develop methods to produce building blocks for metamaterials from nanogold. Electron-beam lithography was used to define an aminosilane patterned chemical template in order to electrostatically self-assemble citrate-capped gold nanoparticles. Equilibrium self-assembly was achieved in 20 minutes by immersing chemical templates into gold nanoparticle solutions. The number of nanoparticles that self-assembled on an aminosilane dot was controlled by manipulating the diameters of the dots and nanoparticles. Adding salt to the nanoparticle solution enabled the nanoparticles to self-assemble in greater numbers on the same sized dot. However, the preparation of the nanoparticle solution containing salt was sensitive to spikes in the salt concentration which led to aggregation of the nanoparticles and non-specific deposition. Gold nanorods were also electrostatically self-assembled. Polyelectrolyte-coated gold nanorods were patterned with limited success. A polyelectrolyte chemical template also patterned gold nanorods, but the gold nanorods preferred to pattern on the edges of the pattern. Ligand-exchanged gold nanorods displayed the best self-assembly, but suffered from slow kinetics. Self-assembled gold nanoparticles were cross-linked with poly(diallyldimethylammonium chloride). The poly(diallyldimethylammonium chloride) allowed additional nanoparticles to pattern on top of the already patterned nanoparticles. Cross-linked nanoparticles were lifted-off of the substrate by sonication in a sodium hydroxide solution. The presence of van der Waals forces and/or amine bonding prevent the nanogold from lifting-off without sonication. A good-solvent evaporation process was used to self-assemble poly(styrene) coated gold nanoparticles into spherical microbead assemblies. The use of larger nanoparticles and larger poly(styrene) ligands resulted in larger and smaller assemblies, respectively. Stirring the solution resulted in a wider size distribution of microbead assemblies due to the stirring's shear forces. Two undeveloped methods to self-assemble nanogold were investigated. One method used block-copolymer thin films as chemical templates to direct the electrostatic self-assembly of nanogold. Another method used gold nanorods that are passivated with different ligands on different faces. The stability of an alkanethiol ligand in different acids and bases was investigated to determine which materials could be used to produce Janus nanorods.
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Silver baits for the "miraculous draught" of amphiphilic lanthanide helicates.
Terazzi, Emmanuel; Guénée, Laure; Varin, Johan; Bocquet, Bernard; Lemonnier, Jean-François; Emery, Daniel; Mareda, Jiri; Piguet, Claude
2011-01-03
The axial connection of flexible thioalkyls chains of variable length (n=1-12) within the segmental bis-tridentate 2-benzimidazole-8-hydroxyquinoline ligands [L12(Cn) -2 H](2-) provides amphiphilic receptors designed for the synthesis of neutral dinuclear lanthanides helicates. However, the stoichiometric mixing of metals and ligands in basic media only yields intricate mixtures of poorly soluble aggregates. The addition of Ag(I) in solution restores classical helicate architectures for n=3, with the quantitative formation of the discrete D(3) -symmetrical [Ln(2) Ag2(L12(C3) -2 H)(3) ](2+) complexes at millimolar concentration (Ln=La, Eu, Lu). The X-ray crystal structure supports the formation of [La(2) Ag(2) (L12(C3) -2 H)(3) ][OTf](2) , which exists in the solid state as infinite linear polymers bridged by S-Ag-S bonds. In contrast, molecular dynamics (MD) simulations in the gas phase and in solution confirm the experimental diffusion measurements, which imply the formation of discrete molecular entities in these media, in which the sulfur atoms of each lipophilic ligand are rapidly exchanged within the Ag(I) coordination sphere. Turned as a predictive tool, MD suggests that this Ag(I) templating effect is efficient only for n=1-3, while for n>3 very loose interactions occur between Ag(I) and the thioalkyl residues. The subsequent experimental demonstration that only 25 % of the total ligand speciation contributes to the formation of [Ln(2) Ag(2) (L12(C12) -2 H)(3) ](2+) in solution puts the bases for a rational approach for the design of amphiphilic helical complexes with predetermined molecular interfaces. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Optical and electronic properties of self-assembled nanoparticle-ligand metasurfaces
NASA Astrophysics Data System (ADS)
Fontana, Jake; Livenere, John; Caldwell, Joshua; Spillmann, Christopher; Naciri, Jawad; Rendell, Ronald; Ratna, Banahalli
2013-03-01
The optical and electronic properties of inorganic nanoparticles organized into two-dimensional lattices sensitively depend on the properties of the organic ligand shell coating the nanoparticles. We study the optical and electronic properties of these two-dimensional metasurfaces consisting of gold nanoparticles functionalized with ligands and self-assembled into macroscopic monolayers on non-templated substrates. Using these metasurfaces we demonstrate an average surface-enhanced Raman scattering (SERS) enhancement factor on the order of 108 for benzenethiol ligands and study the mechanisms that influence the enhancement. These metasurfaces may provide a platform for the development of low-power, low-cost next-generation chem/bio-sensors and new insights into the organic-inorganic interface at the nanoscale. This work was supported with funding provided from the Office of Naval Research
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Molecular Recognition of Corticotropin releasing Factor by Its G protein-coupled Receptor CRFR1
DOE Office of Scientific and Technical Information (OSTI.GOV)
Pioszak, Augen A.; Parker, Naomi R.; Suino-Powell, Kelly
2009-01-15
The bimolecular interaction between corticotropin-releasing factor (CRF), a neuropeptide, and its type 1 receptor (CRFR1), a class B G-protein-coupled receptor (GPCR), is crucial for activation of the hypothalamic-pituitary-adrenal axis in response to stress, and has been a target of intense drug design for the treatment of anxiety, depression, and related disorders. As a class B GPCR, CRFR1 contains an N-terminal extracellular domain (ECD) that provides the primary ligand binding determinants. Here we present three crystal structures of the human CRFR1 ECD, one in a ligand-free form and two in distinct CRF-bound states. The CRFR1 ECD adopts the alpha-beta-betaalpha fold observedmore » for other class B GPCR ECDs, but the N-terminal alpha-helix is significantly shorter and does not contact CRF. CRF adopts a continuous alpha-helix that docks in a hydrophobic surface of the ECD that is distinct from the peptide-binding site of other class B GPCRs, thereby providing a basis for the specificity of ligand recognition between CRFR1 and other class B GPCRs. The binding of CRF is accompanied by clamp-like conformational changes of two loops of the receptor that anchor the CRF C terminus, including the C-terminal amide group. These structural studies provide a molecular framework for understanding peptide binding and specificity by the CRF receptors as well as a template for designing potent and selective CRFR1 antagonists for therapeutic applications.« less
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Homology modeling a fast tool for drug discovery: current perspectives.
Vyas, V K; Ukawala, R D; Ghate, M; Chintha, C
2012-01-01
Major goal of structural biology involve formation of protein-ligand complexes; in which the protein molecules act energetically in the course of binding. Therefore, perceptive of protein-ligand interaction will be very important for structure based drug design. Lack of knowledge of 3D structures has hindered efforts to understand the binding specificities of ligands with protein. With increasing in modeling software and the growing number of known protein structures, homology modeling is rapidly becoming the method of choice for obtaining 3D coordinates of proteins. Homology modeling is a representation of the similarity of environmental residues at topologically corresponding positions in the reference proteins. In the absence of experimental data, model building on the basis of a known 3D structure of a homologous protein is at present the only reliable method to obtain the structural information. Knowledge of the 3D structures of proteins provides invaluable insights into the molecular basis of their functions. The recent advances in homology modeling, particularly in detecting and aligning sequences with template structures, distant homologues, modeling of loops and side chains as well as detecting errors in a model contributed to consistent prediction of protein structure, which was not possible even several years ago. This review focused on the features and a role of homology modeling in predicting protein structure and described current developments in this field with victorious applications at the different stages of the drug design and discovery.
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Homology Modeling a Fast Tool for Drug Discovery: Current Perspectives
Vyas, V. K.; Ukawala, R. D.; Ghate, M.; Chintha, C.
2012-01-01
Major goal of structural biology involve formation of protein-ligand complexes; in which the protein molecules act energetically in the course of binding. Therefore, perceptive of protein-ligand interaction will be very important for structure based drug design. Lack of knowledge of 3D structures has hindered efforts to understand the binding specificities of ligands with protein. With increasing in modeling software and the growing number of known protein structures, homology modeling is rapidly becoming the method of choice for obtaining 3D coordinates of proteins. Homology modeling is a representation of the similarity of environmental residues at topologically corresponding positions in the reference proteins. In the absence of experimental data, model building on the basis of a known 3D structure of a homologous protein is at present the only reliable method to obtain the structural information. Knowledge of the 3D structures of proteins provides invaluable insights into the molecular basis of their functions. The recent advances in homology modeling, particularly in detecting and aligning sequences with template structures, distant homologues, modeling of loops and side chains as well as detecting errors in a model contributed to consistent prediction of protein structure, which was not possible even several years ago. This review focused on the features and a role of homology modeling in predicting protein structure and described current developments in this field with victorious applications at the different stages of the drug design and discovery. PMID:23204616
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Piperine: researchers discover new flavor in an ancient spice.
Szallasi, Arpad
2005-09-01
Studies with animals that are deficient in the vanilloid (capsaicin) receptor TRPV1 have confirmed the pivotal role that TRPV1 has in the development of post-inflammatory hyperalgesia, and enhanced TRPV1 expression has been described in various human disorders. Natural products have provided several lead structures for the development of vanilloid ligands. A recent study shows that piperine, the irritant principle in black pepper, is more efficient than capsaicin in the desensitization of human TRPV1, which suggests that this pharmacological aspect of vanilloids can be dissociated from its potency. This finding raises the intriguing possibility that piperine can be used as a chemical template for the design of improved TRPV1 agonists.
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Baum, Bernhard; Lecker, Laura S. M.; Zoltner, Martin; Jaenicke, Elmar; Schnell, Robert; Hunter, William N.; Brenk, Ruth
2015-01-01
Bacterial infections remain a serious health concern, in particular causing life-threatening infections of hospitalized and immunocompromised patients. The situation is exacerbated by the rise in antibacterial drug resistance, and new treatments are urgently sought. In this endeavour, accurate structures of molecular targets can support early-stage drug discovery. Here, crystal structures, in three distinct forms, of recombinant Pseudomonas aeruginosa β-ketoacyl-(acyl-carrier-protein) synthase II (FabF) are presented. This enzyme, which is involved in fatty-acid biosynthesis, has been validated by genetic and chemical means as an antibiotic target in Gram-positive bacteria and represents a potential target in Gram-negative bacteria. The structures of apo FabF, of a C164Q mutant in which the binding site is altered to resemble the substrate-bound state and of a complex with 3-(benzoylamino)-2-hydroxybenzoic acid are reported. This compound mimics aspects of a known natural product inhibitor, platensimycin, and surprisingly was observed binding outside the active site, interacting with a symmetry-related molecule. An unusual feature is a completely buried potassium-binding site that was identified in all three structures. Comparisons suggest that this may represent a conserved structural feature of FabF relevant to fold stability. The new structures provide templates for structure-based ligand design and, together with the protocols and reagents, may underpin a target-based drug-discovery project for urgently needed antibacterials. PMID:26249693
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Malo, Marcus; Persson, Ronnie; Svensson, Peder; Luthman, Kristina; Brive, Lars
2013-03-01
Prediction of 3D structures of membrane proteins, and of G-protein coupled receptors (GPCRs) in particular, is motivated by their importance in biological systems and the difficulties associated with experimental structure determination. In the present study, a novel method for the prediction of 3D structures of the membrane-embedded region of helical membrane proteins is presented. A large pool of candidate models are produced by repacking of the helices of a homology model using Monte Carlo sampling in torsion space, followed by ranking based on their geometric and ligand-binding properties. The trajectory is directed by weak initial restraints to orient helices towards the original model to improve computation efficiency, and by a ligand to guide the receptor towards a chosen conformational state. The method was validated by construction of the β1 adrenergic receptor model in complex with (S)-cyanopindolol using bovine rhodopsin as template. In addition, models of the dopamine D2 receptor were produced with the selective and rigid agonist (R)-N-propylapomorphine ((R)-NPA) present. A second quality assessment was implemented by evaluating the results from docking of a library of 29 ligands with known activity, which further discriminated between receptor models. Agonist binding and recognition by the dopamine D2 receptor is interpreted using the 3D structure model resulting from the approach. This method has a potential for modeling of all types of helical transmembrane proteins for which a structural template with sequence homology sufficient for homology modeling is not available or is in an incorrect conformational state, but for which sufficient empirical information is accessible.
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Anuradha, C M; Mulakayala, Chaitanya; Babajan, Banaganapalli; Naveen, M; Rajasekhar, Chikati; Kumar, Chitta Suresh
2010-01-01
Multi drug resistance capacity for Mycobacterium tuberculosis (MDR-Mtb) demands the profound need for developing new anti-tuberculosis drugs. The present work is on Mtb-MurC ligase, which is an enzyme involved in biosynthesis of peptidoglycan, a component of Mtb cell wall. In this paper the 3-D structure of Mtb-MurC has been constructed using the templates 1GQQ and 1P31. Structural refinement and energy minimization of the predicted Mtb-MurC ligase model has been carried out by molecular dynamics. The streochemical check failures in the energy minimized model have been evaluated through Procheck, Whatif ProSA, and Verify 3D. Further torsion angles for the side chains of amino acid residues of the developed model were determined using Predictor. Docking analysis of Mtb-MurC model with ligands and natural substrates enabled us to identify specific residues viz. Gly125, Lys126, Arg331, and Arg332, within the Mtb-MurC binding pocket to play an important role in ligand and substrate binding affinity and selectivity. The availability of Mtb-MurC ligase built model, together with insights gained from docking analysis will promote the rational design of potent and selective Mtb-MurC ligase inhibitors as antituberculosis therapeutics.
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NASA Astrophysics Data System (ADS)
Paulino, M.; Esteves, A.; Vega, M.; Tabares, G.; Ehrlich, R.; Tapia, O.
1998-07-01
EgDf1 is a developmentally regulated protein from the parasite Echinococcus granulosus related to a family of hydrophobic ligand binding proteins. This protein could play a crucial role during the parasite life cycle development since this organism is unable to synthetize most of their own lipids de novo. Furthermore, it has been shown that two related protein from other parasitic platyhelminths (Fh15 from Fasciola hepatica and Sm14 from Schistosoma mansoni) are able to confer protective inmunity against experimental infection in animal models. A three-dimensional structure would help establishing structure/function relationships on a knowledge based manner. 3D structures for EgDf1 protein were modelled by using myelin P2 (mP2) and intestine fatty acid binding protein (I-FABP) as templates. Molecular dynamics techniques were used to validate the models. Template mP2 yielded the best 3D structure for EgDf1. Palmitic and oleic acids were docked inside EgDf1. The present theoretical results suggest definite location in the secondary structure of the epitopic regions, consensus phosphorylation motifs and oleic acid as a good ligand candidate to EgDf1. This protein might well be involved in the process of supplying hydrophobic metabolites for membrane biosynthesis and for signaling pathways.
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Pai, Priyadarshini P; Dattatreya, Rohit Kadam; Mondal, Sukanta
2017-11-01
Enzyme interactions with ligands are crucial for various biochemical reactions governing life. Over many years attempts to identify these residues for biotechnological manipulations have been made using experimental and computational techniques. The computational approaches have gathered impetus with the accruing availability of sequence and structure information, broadly classified into template-based and de novo methods. One of the predominant de novo methods using sequence information involves application of biological properties for supervised machine learning. Here, we propose a support vector machines-based ensemble for prediction of protein-ligand interacting residues using one of the most important discriminative contributing properties in the interacting residue neighbourhood, i. e., evolutionary information in the form of position-specific- scoring matrix (PSSM). The study has been performed on a non-redundant dataset comprising of 9269 interacting and 91773 non-interacting residues for prediction model generation and further evaluation. Of the various PSSM-based models explored, the proposed method named ROBBY (pRediction Of Biologically relevant small molecule Binding residues on enzYmes) shows an accuracy of 84.0 %, Matthews Correlation Coefficient of 0.343 and F-measure of 39.0 % on 78 test enzymes. Further, scope of adding domain knowledge such as pocket information has also been investigated; results showed significant enhancement in method precision. Findings are hoped to boost the reliability of small-molecule ligand interaction prediction for enzyme applications and drug design. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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The Preparation of an Ultrastable Mesoporous Cr(III)-MOF via Reductive Labilization
2015-09-02
of metal clusters from a template MOF with a known structure. Fe(III)-MOFs can serve as practical structural templates because iron resembles chromium ...clusters in PCN-333 are able to accommodate both di- and trivalent metal ions by varying the charges of the terminal ligands, the bridging oxygen atoms, and...molecules in trivalent aqua complexes27 Inert complexes Labile complexes M(OH2) Cr(OH2)6 3+ Ir(OH2)6 3+ V(OH2)6 3+ Fe(OH2)6 3+ Ti(OH2)6 3+ k (s1) 2.4 10
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Huang, Hongliang; Li, Jian-Rong; Wang, Keke; Han, Tongtong; Tong, Minman; Li, Liangsha; Xie, Yabo; Yang, Qingyuan; Liu, Dahuan; Zhong, Chongli
2015-01-01
Metal-organic frameworks (MOFs) have recently emerged as a new type of nanoporous materials with tailorable structures and functions. Usually, MOFs have uniform pores smaller than 2 nm in size, limiting their practical applications in some cases. Although a few approaches have been adopted to prepare MOFs with larger pores, it is still challenging to synthesize hierarchical-pore MOFs (H-MOFs) with high structural controllability and good stability. Here we demonstrate a facile and versatile method, an in situ self-assembly template strategy for fabricating stable H-MOFs, in which multi-scale soluble and/or acid-sensitive metal-organic assembly (MOA) fragments form during the reactions between metal ions and organic ligands (to construct MOFs), and act as removable dynamic chemical templates. This general strategy was successfully used to prepare various H-MOFs that show rich porous properties and potential applications, such as in large molecule adsorption. Notably, the mesopore sizes of the H-MOFs can be tuned by varying the amount of templates. PMID:26548441
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Nørager, Niels G; Jensen, Christel B; Rathje, Mette; Andersen, Jacob; Madsen, Kenneth L; Kristensen, Anders S; Strømgaard, Kristian
2013-09-20
The natural product argiotoxin-636 (ArgTX-636) found in the venom of the Argiope lobata spider is a potent open-channel blocker of ionotropic glutamate (iGlu) receptors, and recently, two analogues, ArgTX-75 and ArgTX-48, were identified with increased potency and selectivity for iGlu receptor subtypes. Here, we have exploited these analogues as templates in the development of fluorescent iGlu receptor ligands to be employed as unique tools for dynamic studies. Eighteen fluorescent analogues were designed and synthesized, and subsequently pharmacologically evaluated at three iGlu receptor subtypes, which resulted in the discovery of highly potent fluorescent iGlu receptor antagonists with IC50 values as low as 11 nM. The most promising ligands were further characterized showing retention of their mechanism of action, as open-channel blockers of iGlu receptors, as well as preservation of the photophysical properties of the incorporated fluorophores. Finally, we demonstrate the applicability of the developed probes for imaging of iGlu receptors in hippocampal neurons.
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Beyond Antibodies as Binding Partners: The Role of Antibody Mimetics in Bioanalysis.
Yu, Xiaowen; Yang, Yu-Ping; Dikici, Emre; Deo, Sapna K; Daunert, Sylvia
2017-06-12
The emergence of novel binding proteins or antibody mimetics capable of binding to ligand analytes in a manner analogous to that of the antigen-antibody interaction has spurred increased interest in the biotechnology and bioanalytical communities. The goal is to produce antibody mimetics designed to outperform antibodies with regard to binding affinities, cellular and tumor penetration, large-scale production, and temperature and pH stability. The generation of antibody mimetics with tailored characteristics involves the identification of a naturally occurring protein scaffold as a template that binds to a desired ligand. This scaffold is then engineered to create a superior binder by first creating a library that is then subjected to a series of selection steps. Antibody mimetics have been successfully used in the development of binding assays for the detection of analytes in biological samples, as well as in separation methods, cancer therapy, targeted drug delivery, and in vivo imaging. This review describes recent advances in the field of antibody mimetics and their applications in bioanalytical chemistry, specifically in diagnostics and other analytical methods.
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NASA Astrophysics Data System (ADS)
Paraginski, Gustavo Luiz; Hörner, Manfredo; Back, Davi Fernando; Wohlmuth Alves dos Santos, Aline Joana Rolina; Beck, Johannes
2016-01-01
Deprotonated triazene N-oxides are able to chelate metal ions resulting in five-membered rings without carbon atoms. A new ligand 1-(2-biphenyl)-3-methyltriazenide-N-oxide (1) and its mononuclear Cu(II) complex (2) were synthesized to verify the capability of this ligand to promote Cu(II)⋯arene-π interactions. Ligand 1 and complex 2 have been characterized by elemental analysis, mass spectrometry (ESI(+)-TOF), IR, and UV-Vis spectroscopy. In addition, ligand 1 was characterized by 1H and 13C NMR and complex 2 by X-ray diffraction on single crystal. The crystal structure of complex 2 reveals a distorted tetrahedral geometry of Cu(II) in the first coordination sphere, which expands to a distorted octahedral environment by two symmetrically independent intramolecular metal⋯arene-π interactions. These interactions are provided by ortho-phenyl rings of both triazene N-oxide ligands 1. The aim of this work was to contribute to the architecture of new Cu(II)⋯arene-π complexes based on the synthesis of appropriated ligand for intramolecular interactions
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Labview virtual instruments for calcium buffer calculations.
Reitz, Frederick B; Pollack, Gerald H
2003-01-01
Labview VIs based upon the calculator programs of Fabiato and Fabiato (J. Physiol. Paris 75 (1979) 463) are presented. The VIs comprise the necessary computations for the accurate preparation of multiple-metal buffers, for the back-calculation of buffer composition given known free metal concentrations and stability constants used, for the determination of free concentrations from a given buffer composition, and for the determination of apparent stability constants from absolute constants. As implemented, the VIs can concurrently account for up to three divalent metals, two monovalent metals and four ligands thereof, and the modular design of the VIs facilitates further extension of their capacity. As Labview VIs are inherently graphical, these VIs may serve as useful templates for those wishing to adapt this software to other platforms.
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Androutsou, Maria-Eleni; Saifeddine, Mahmoud; Hollenberg, Morley D; Matsoukas, John; Agelis, George
2010-04-01
In the present study, we report the synthesis and biological evaluation of a series of new non-peptide PAR(1) mimetic receptor antagonists, based on conformational analysis of the S(42)FLLR(46) tethered ligand (TL) sequence of PAR(1). These compounds incorporate the key pharmacophore groups in the TL sequence, guanidyl, amino and phenyl, which are essential for triggering receptor activity. Compounds 5 and 15 (50-100 microM) inhibited both TFLLR-amide (10 microM) and thrombin-mediated (0.5 and 1 U/ml; 5 and 10 microM) calcium signaling in a cultured human HEK cell assay.
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Chu, Qianli; Duncan, Andrew J E; Papaefstathiou, Giannis S; Hamilton, Tamara D; Atkinson, Manza B J; Mariappan, S V Santhana; MacGillivray, Leonard R
2018-04-11
Enlargement of a self-assembled metal-organic rhomboid is achieved via the organic solid state. The solid-state synthesis of an elongated organic ligand was achieved by a template directed [2 + 2] photodimerization in a cocrystal. Initial cocrystals obtained of resorcinol template and reactant alkene afforded a 1:2 cocrystal with the alkene in a stacked yet photostable geometry. Cocrystallization performed in the presence of excess template resulted in a 3:2 cocrystal composed of novel discrete 10-component hydrogen-bonded "superassemblies" wherein the alkenes undergo a head-to-head [2 + 2] photodimerization. Isolation and reaction of elongated photoproduct with Cu(II) ions afforded a metal-organic rhomboid of nanoscale dimensions that hosts small molecules in the solid state as guests.
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NASA Astrophysics Data System (ADS)
Gao, Zhe
This dissertation presents the synthesis and characterization of several novel inorganic and hybrid nanoparticles, including the bio-compatible boron nanoparticles (BNPs) for boron neutron capture therapy (BNCT), tannic acid-templated mesoporous silica nanoparticles and degradable bridged silsesquioxane silica nanoparticles. Chapter 1 provides background information of BNCT and reviews the development of design and synthesizing silica nanoparticles and the study of silica material degradability. Chapter 2 describes the preparation and characterization of dopamine modified BNPs and the preliminary cell study of them. The BNPs were first produced via ball milling, with fatty acid on the surface to stabilize the combustible boron elements. This chapter will mainly focus on the ligand-exchange strategy, in which the fatty acids were replaced by non-toxic dopamines in a facile one-pot reaction. The dopamine-coated BNPs (DA-BNPs) revealed good water dispersibility and low cytotoxicity. Chapter 3 describes the synthesis of tannic acid template mesoporous silica nanoparticles (TA-TEOS SiNPs) and their application to immobilize proteins. The monodispersed TA SiNPs with uniform pore size up to approximately 13 nm were produced by utilizing tannic acid as a molecular template. We studied the influence of TA concentration and reaction time on the morphology and pore size of the particles. Furthermore, the TA-TEOS particles could subsequently be modified with amine groups allowing them to be capable of incorporating imaging ligands and other guest molecules. The ability of the TA-TEOS particles to store biomolecules was preliminarily assessed with three proteins of different charge characteristics and dimensions. The immobilization of malic dehydrogenase on TA-TEOS enhanced the stability of the enzyme at room temperature. Chapter 4 details the synthesis of several bridged silsesquioxanes and the preparation of degradable hybrid SiNPs via co-condensation of bridged silsesquioxanes with tetraethoxysilane. In vivo studies show that the solid SiNPs accumulate in many organs due to the lack of degradability. The aim of our work is to address this shortcoming by producing novel degradable SiNPs. Bridged silsesquioxanes were used as the precursors of the particles, and upon cleavage of the carbamate groups when brought into contact with aqueous media, the particles degraded into porous structures.
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Sun, Jie; Sun, Di; Yuan, Shuai; Tian, Dongxu; Zhang, Liangliang; Wang, Xingpo; Sun, Daofeng
2012-12-14
A series of C(3i)-symmetric bicapped trigonal antiprismatic Cd(8) cages [2X@Cd(8)L(6)(H(2)O)(6)]⋅n Y⋅solvents (X = Cl(-), Y = NO(3)(-), n = 2: MOCC-4; X = Br(-), Y = NO(3)(-), n = 2: MOCC-5; X = NO(3)(-), Y = NO(3)(-), n = 2: MOCC-6; X = NO(3)(-), Y = BF(4)(-), n = 2: MOCC-7; X = NO(3)(-), Y = ClO(4)(-), n = 2: MOCC-8; X = CO(3)(2-), n = 0: MOCC-9), doubly anion templated by different anions, were solvothermally synthesized by means of a flexible ligand. Interestingly, the CO(3)(2-) template for MOCC-9 was generated in situ by two-step decomposition of DMF solvent. For other MOCCs, spherical or trigonal monovalent anions could also play the role of template in their formation. The template abilities of these anions in the formation of the cages were experimentally studied and are discussed for the first time. Anion exchange of MOCC-8 was carried out and showed anion-size selectivity. All of the cage-like compounds emit strong luminescence at room temperature. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Synthesis, characterization and solid-state properties of [Zn(Hdmmthiol)2]\\cdot2H2O complex
NASA Astrophysics Data System (ADS)
Dagdelen, Fethi; Aydogdu, Yildirim; Dey, Kamalendu; Biswas, Susobhan
2016-05-01
The zinc(II) complex with tridentate thiohydrazone ligand have been prepared by metal template reaction. The metal template reaction was used to prepare the zinc (II) complex with tridentate thiohydrazone ligand. The reaction of diacetylmonoxime and, morpholine N-thiohydrazidewith Zn(OAc)2 \\cdot2H2O under reflux yielded the formation of the [Zn(Hdmmthiol )2]\\cdot2H2O complex. The complex was characterized by a combination of protocols including elemental analysis, UV+vis, FT-IR, TG and PXRD. The temperature dependence of the electrical conductivity and the optical property of the [Zn(Hdmmthiol )2] \\cdot2H2O complex is called H2dammthiol was studied. Powder X-ray diffraction (PXRD) method was used to investigate the crystal structure of the sample. The zinc complex was shown to be a member of the triclinic system. The zinc complex was determined to have n-type conductivity as demonstrated in the hot probe measurements. The complex was determined to display direct optical transition with band gaps of 2.52eV as determined by the optical absorption analysis.
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Todorovic, Aleksandar; Lensing, Cody J; Holder, Jerry Ryan; Scott, Joseph W; Sorensen, Nicholas B; Haskell-Luevano, Carrie
2018-05-21
The melanocortin system regulates an array of diverse physiological functions including pigmentation, feeding behavior, energy homeostasis, cardiovascular regulation, sexual function, and steroidogenesis. Endogenous melanocortin agonist ligands all possess the minimal messaging tetrapeptide sequence His-Phe-Arg-Trp. Based on this endogenous sequence, the Ac-His1-DPhe2-Arg3-Trp4-NH 2 tetrapeptide has previously been shown to be a useful scaffold when utilizing traditional positional scanning approaches to modify activity at the various melanocortin receptors (MC1-5R). The study reported herein was undertaken to evaluate a double simultaneous substitution strategy as an approach to further diversify the Ac-His1-DPhe2-Arg3-Trp4-NH 2 tetrapeptide with concurrent introduction of natural and unnatural amino acids at positions 1, 2, or 4 as well as an octanoyl residue at the N-terminus. The designed library includes the following combinations: (A) double simultaneous substitution at capping group position (Ac) together with position 1, 2, or 4, (B) double simultaneous substitution at position 1 and 2, (C) double simultaneous substitution at position 1 and 4, and (D) double simultaneous substitution at position 2 and 4. Several lead ligands with unique pharmacologies were discovered in the current study including antagonists targeting the neuronal mMC3R with minimal agonist activity and ligands with selective profiles for the various melanocortin subtypes. The results suggest that the double simultaneous substitution strategy is a suitable approach in altering melanocortin receptor potency, selectivity, or converting agonists into antagonists and vice versa.
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NASA Astrophysics Data System (ADS)
Surekha, Kanagarajan; Nachiappan, Mutharasappan; Prabhu, Dhamodharan; Choubey, Sanjay Kumar; Biswal, Jayashree; Jeyakanthan, Jeyaraman
2017-01-01
Dihydroorotate dehydrogenase (DHODH) plays a major role in the rate limiting step of de novo pyrimidine biosynthesis pathway and it is pronounced as a novel target for drug development of cancer. The currently available drugs against DHODH are ineffective and bear various side effects. Three-dimensional structure of the targeted protein was constructed using molecular modeling approach followed by 100 ns molecular dynamics simulations. In this study, High Throughput Virtual Screening (HTVS) was performed using various compound libraries to identify pharmacologically potential molecules. The top four identified lead molecules includes NCI_47074, HitFinder_7630, Binding_66981 and Specs_108872 with high docking score of -9.45, -8.29, -8.04 and -8.03 kcal/mol and the corresponding binding free energy were -16.25, -56.37, -26.93 and -48.04 kcal/mol respectively. Arg122, Arg185, Glu255 and Gly257 are the key residues found to be interacting with the ligands. Molecular dynamics simulations of DHODH-inhibitors complexes were performed to assess the stability of various conformations from complex structures of TtDHODH. Furthermore, stereoelectronic features of the ligands were explored to facilitate charge transfer during the protein-ligand interactions using Density Functional Theoretical approach. Based on in silico analysis, the ligand NCI_47074 ((2Z)-3-({6-[(2Z)-3-carboxylatoprop-2-enamido]pyridin-2-yl}carbamoyl)prop-2-enoate) was found to be the most potent lead molecule which was validated using energetic and electronic parameters and it could serve as a template for designing effective anticancerous drug molecule.
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Ten Steps to Create Virtual Smile Design Templates With Adobe Photoshop® CS6.
Sundar, Manoj Kumar; Chelliah, Venkataraman
2018-03-01
Computer design software has become a primary tool for communication among the dentist, patient, and ceramist. Virtual smile design can be carried out using various software programs, most of which use assorted forms of teeth templates that are made based on the concept of "golden proportion." Despite current advances in 3-dimensional imaging and smile designing, many clinicians still employ conventional design methods and analog (ie, man-made) mock-ups in assessing and establishing esthetic makeovers. To simplify virtual smile designing, the teeth templates should be readily available. No literature has provided details as to how to create these templates. This article explains a technique for creating different forms of teeth templates using Adobe Photoshop® CS6 that eventually can be used for smile design purposes, either in Photoshop or Microsoft Powerpoint. Clinically speaking, various smile design templates created using set proportions in Adobe Photoshop CS6 can be used in virtual smile designing, a valuable resource in diagnosis, treatment planning, and communicating with patients and ceramists, thus providing a platform for a successful esthetic rehabilitation.
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CYPSI: a structure-based interface for cytochrome P450s and ligands in Arabidopsis thaliana
2012-01-01
Background The cytochrome P450 (CYP) superfamily enables terrestrial plants to adapt to harsh environments. CYPs are key enzymes involved in a wide range of metabolic pathways. It is particularly useful to be able to analyse the three-dimensional (3D) structure when investigating the interactions between CYPs and their substrates. However, only two plant CYP structures have been resolved. In addition, no currently available databases contain structural information on plant CYPs and ligands. Fortunately, the 3D structure of CYPs is highly conserved and this has made it possible to obtain structural information from template-based modelling (TBM). Description The CYP Structure Interface (CYPSI) is a platform for CYP studies. CYPSI integrated the 3D structures for 266 A. thaliana CYPs predicted by three TBM methods: BMCD, which we developed specifically for CYP TBM; and two well-known web-servers, MUSTER and I-TASSER. After careful template selection and optimization, the models built by BMCD were accurate enough for practical application, which we demonstrated using a docking example aimed at searching for the CYPs responsible for ABA 8′-hydroxylation. CYPSI also provides extensive resources for A. thaliana CYP structure and function studies, including 400 PDB entries for solved CYPs, 48 metabolic pathways associated with A. thaliana CYPs, 232 reported CYP ligands and 18 A. thaliana CYPs docked with ligands (61 complexes in total). In addition, CYPSI also includes the ability to search for similar sequences and chemicals. Conclusions CYPSI provides comprehensive structure and function information for A. thaliana CYPs, which should facilitate investigations into the interactions between CYPs and their substrates. CYPSI has a user-friendly interface, which is available at http://bioinfo.cau.edu.cn/CYPSI. PMID:23256889
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Xiao, Xian; He, Qiang-Hua; Yu, Li-Yan; Wang, Song-Qing; Li, Yang; Yang, Hua; Zhang, Ai-Hua; Ma, Xiao-Hong; Peng, Yu-Jie; Chen, Bing
2017-02-01
The PTP non-receptor type 4 (PTPN4) is an important regulator protein in learning, spatial memory and cerebellar synaptic plasticity; targeting the PDZ domain of PTPN4 has become as attractive therapeutic strategy for human neuroglioma. Here, we systematically examined the complex crystal structures of PTPN4 PDZ domain with its known peptide ligands; a number of charged amino acid residues were identified in these ligands and in the peptide-binding pocket of PDZ domain, which can constitute a complicated salt-bridge network across the complex interface. Molecular dynamics (MD) simulations, binding free energy calculations and continuum model analysis revealed that the electrostatic effect plays a predominant role in domain-peptide binding, while other noncovalent interactions such as hydrogen bonds and hydrophobic forces are also responsible for the binding. The computational findings were then used to guide structure-based optimization of the interfacial salt-bridge network. Consequently, five peptides were rationally designed using the high-affinity binder Cyto8-RETEV (RETEV -COOH ) as template, including four single-point mutants (i.e. Cyto8-mtxe 0 : RETEE -COOH , Cyto8-mtxd -1 : RETDV -COOH , Cyto8-mtxd -3 : RDTEV -COOH and Cyto8-mtxk -4 : KETEV -COOH ) and one double-point mutant (i.e. Cyto8-mtxd -1 k -4 : KETDV -COOH ). Binding assays confirmed that three (Cyto8-mtxd -1 , Cyto8-mtxk -4 and Cyto8-mtxd -1 k -4 ) out of the five designed peptides exhibit moderately or considerably increased affinity as compared to the native peptide Cyto8-RETEV. Copyright © 2016 Elsevier Ltd. All rights reserved.
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Laha, Joydev K; Sharma, Shubhra; Kirar, Seema; Banerjee, Uttam C
2017-09-15
A de novo design and synthesis of N-heteroaryl-fused vinyl sultams as templates for programming chemical reactions on vinyl sultam periphery or (hetero)aryl ring is described. The key features include rational designing and sustainable synthesis of the template, customized reactions of vinyl sultams at C═C bond or involving N-S bond cleavage, and reactions on the periphery of the heteroaryl ring for late-stage diversification. The simple, easy access to the template coupled with opportunities for the synthesis of diversely functionalized heterocyles from a single template constitutes a rare study in contemporary organic synthesis.
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Wave Energy Prize - General Information
Scharmen, Wesley
2016-12-01
All the informational files, templates, rules and guidelines for Wave Energy Prize (WEP), including the Wave Energy Prize Rules, Participant Terms and Conditions Template, WEC Prize Name, Logo, Branding, WEC Publicity, Technical Submission Template , Numerical Modeling Template, SSTF Submission Template, 1/20th Scale Model Design and Construction Plan Template, Final Report template, and Webinars.
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Chen, Xiaojun; Xu, Lu; Wang, Wei; Li, Xing; Sun, Yi; Politis, Constantinus
2016-09-01
The surgical template is a guide aimed at directing the implant placement, tumor resection, osteotomy and bone repositioning. Using it, preoperative planning can be transferred to the actual surgical site, and the precision, safety and reliability of the surgery can be improved. However, the actual workflow of the surgical template design and manufacturing is quite complicated before the final clinical application. The major goal of the paper is to provide a comprehensive reference source of the current and future development of the template design and manufacturing for relevant researchers. Expert commentary: This paper aims to present a review of the necessary procedures in the template-guided surgery including the image processing, 3D visualization, preoperative planning, surgical guide design and manufacturing. In addition, the template-guided clinical applications for various kinds of surgeries are reviewed, and it demonstrated that the precision of the surgery has been improved compared with the non-guided operations.
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Energetics of ligand-receptor binding affinity on endothelial cells: An in vitro model.
Fotticchia, Iolanda; Guarnieri, Daniela; Fotticchia, Teresa; Falanga, Andrea Patrizia; Vecchione, Raffaele; Giancola, Concetta; Netti, Paolo Antonio
2016-08-01
Targeted therapies represent a challenge in modern medicine. In this contest, we propose a rapid and reliable methodology based on Isothermal Titration Calorimetry (ITC) coupled with confluent cell layers cultured around biocompatible templating microparticles to quantify the number of overexpressing receptors on cell membrane and study the energetics of receptor-ligand binding in near-physiological conditions. In the in vitro model here proposed we used the bEnd3 cell line as brain endothelial cells to mimic the blood brain barrier (BBB) cultured on dextran microbeads ranging from 67μm to 80μm in size (Cytodex) and the primary human umbilical vein cells (HUVEC) for comparison. The revealed affinity between transferrin (Tf) and transferrin receptor (TfR) in both systems is very high, Kd values are in the order of nM. Conversely, the value of TfRs/cell reveals a 100-fold increase in the number of TfRs per bEnd3 cells compared to HUVEC cells. The presented methodology can represent a novel and helpful strategy to identify targets, to address drug design and selectively deliver therapeutics that can cross biological barriers such as the blood brain barrier. Copyright © 2016 Elsevier B.V. All rights reserved.
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NASA Astrophysics Data System (ADS)
Cho, Nam-Chul; Seo, Seoung-Hwan; Kim, Dohee; Shin, Ji-Sun; Ju, Jeongmin; Seong, Jihye; Seo, Seon Hee; Lee, Iiyoun; Lee, Kyung-Tae; Kim, Yun Kyung; No, Kyoung Tai; Pae, Ae Nim
2016-08-01
Protease-activated receptor 2 (PAR2) is a G protein-coupled receptor, mediating inflammation and pain signaling in neurons, thus it is considered to be a potential therapeutic target for inflammatory diseases. In this study, we performed a ligand-based virtual screening of 1.6 million compounds by employing a common-feature pharmacophore model and two-dimensional similarity search to identify a new PAR2 antagonist. The common-feature pharmacophore model was established based on the biological screening results of our in-house library. The initial virtual screening yielded a total number of 47 hits, and additional biological activity tests including PAR2 antagonism and anti-inflammatory effects resulted in a promising candidate, compound 43, which demonstrated an IC50 value of 8.22 µM against PAR2. In next step, a PAR2 homology model was constructed using the crystal structure of the PAR1 as a template to explore the binding mode of the identified ligands. A molecular docking method was optimized by comparing the binding modes of a known PAR2 agonist GB110 and antagonist GB83, and applied to predict the binding mode of our hit compound 43. In-depth docking analyses revealed that the hydrophobic interaction with Phe2435.39 is crucial for PAR2 ligands to exert antagonistic activity. MD simulation results supported the predicted docking poses that PAR2 antagonist blocked a conformational rearrangement of Na+ allosteric site in contrast to PAR2 agonist that showed Na+ relocation upon GPCR activation. In conclusion, we identified new a PAR2 antagonist together with its binding mode, which provides useful insights for the design and development of PAR2 ligands.
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Wang, Di; Wang, Yimeng; Wang, Jianhua; Song, Changhui; Yang, Yongqiang; Zhang, Zimian; Lin, Hui; Zhen, Yongqiang; Liao, Suixiang
2016-07-22
In order to meet the clinical requirements of spine surgery, this paper proposes the fabrication of the customized template for spine surgery through computer-aided design. A 3D metal printing-selective laser melting (SLM) technique was employed to directly fabricate the 316L stainless steel template, and the metal template with tiny locating holes was used as an auxiliary tool to insert spinal screws inside the patient's body. To guarantee accurate fabrication of the template for cervical vertebra operation, the contact face was placed upwards to improve the joint quality between the template and the cervical vertebra. The joint surface of the printed template had a roughness of Ra = 13 ± 2 μm. After abrasive blasting, the surface roughness was Ra = 7 ± 0.5 μm. The surgical metal template was bound with the 3D-printed Acrylonitrile Butadiene Styrene (ABS) plastic model. The micro-hardness values determined at the cross-sections of SLM-processed samples varied from HV0.3 250 to HV0.3 280, and the measured tensile strength was in the range of 450 MPa to 560 MPa, which showed that the template had requisite strength. Finally, the metal template was clinically used in the patient's surgical operation, and the screws were inserted precisely as the result of using the auxiliary template. The geometrical parameters of the template hole (e.g., diameter and wall thickness) were optimized, and measures were taken to optimize the key geometrical units (e.g., hole units) in metal 3D printing. Compared to the traditional technology of screw insertion, the use of the surgical metal template enabled the screws to be inserted more easily and accurately during spinal surgery. However, the design of the high-quality template should fully take into account the clinical demands of surgeons, as well as the advice of the designing engineers and operating technicians.
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Design and Fabrication of a Precision Template for Spine Surgery Using Selective Laser Melting (SLM)
Wang, Di; Wang, Yimeng; Wang, Jianhua; Song, Changhui; Yang, Yongqiang; Zhang, Zimian; Lin, Hui; Zhen, Yongqiang; Liao, Suixiang
2016-01-01
In order to meet the clinical requirements of spine surgery, this paper proposes the fabrication of the customized template for spine surgery through computer-aided design. A 3D metal printing-selective laser melting (SLM) technique was employed to directly fabricate the 316L stainless steel template, and the metal template with tiny locating holes was used as an auxiliary tool to insert spinal screws inside the patient’s body. To guarantee accurate fabrication of the template for cervical vertebra operation, the contact face was placed upwards to improve the joint quality between the template and the cervical vertebra. The joint surface of the printed template had a roughness of Ra = 13 ± 2 μm. After abrasive blasting, the surface roughness was Ra = 7 ± 0.5 μm. The surgical metal template was bound with the 3D-printed Acrylonitrile Butadiene Styrene (ABS) plastic model. The micro-hardness values determined at the cross-sections of SLM-processed samples varied from HV0.3 250 to HV0.3 280, and the measured tensile strength was in the range of 450 MPa to 560 MPa, which showed that the template had requisite strength. Finally, the metal template was clinically used in the patient’s surgical operation, and the screws were inserted precisely as the result of using the auxiliary template. The geometrical parameters of the template hole (e.g., diameter and wall thickness) were optimized, and measures were taken to optimize the key geometrical units (e.g., hole units) in metal 3D printing. Compared to the traditional technology of screw insertion, the use of the surgical metal template enabled the screws to be inserted more easily and accurately during spinal surgery. However, the design of the high-quality template should fully take into account the clinical demands of surgeons, as well as the advice of the designing engineers and operating technicians. PMID:28773730
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ERIC Educational Resources Information Center
Sues, Peter E.; Cai, Kuihua; McIntosh, Douglas F.; Morris, Robert H.
2015-01-01
Asymmetric transfer hydrogenation is an important transformation for the production of fine chemicals. Traditionally, platinum group metals are used to catalyze this reaction, but recent pressure for greener practices has driven the development of base-metal catalysts. Due to the growing interest in this area of research, the underlying concepts…
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Thompson, Aaron A.; Liu, Wei; Chun, Eugene
Members of the opioid receptor family of G-protein-coupled receptors (GPCRs) are found throughout the peripheral and central nervous system, where they have key roles in nociception and analgesia. Unlike the 'classical' opioid receptors, {delta}, {kappa} and {mu} ({delta}-OR, {kappa}-OR and {mu}-OR), which were delineated by pharmacological criteria in the 1970s and 1980s, the nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP, also known as ORL-1) was discovered relatively recently by molecular cloning and characterization of an orphan GPCR. Although it shares high sequence similarity with classical opioid GPCR subtypes ({approx}60%), NOP has a markedly distinct pharmacology, featuring activation by the endogenous peptidemore » N/OFQ, and unique selectivity for exogenous ligands. Here we report the crystal structure of human NOP, solved in complex with the peptide mimetic antagonist compound-24 (C-24) (ref. 4), revealing atomic details of ligand-receptor recognition and selectivity. Compound-24 mimics the first four amino-terminal residues of the NOP-selective peptide antagonist UFP-101, a close derivative of N/OFQ, and provides important clues to the binding of these peptides. The X-ray structure also shows substantial conformational differences in the pocket regions between NOP and the classical opioid receptors {kappa} (ref. 5) and {mu} (ref. 6), and these are probably due to a small number of residues that vary between these receptors. The NOP-compound-24 structure explains the divergent selectivity profile of NOP and provides a new structural template for the design of NOP ligands.« less
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Indole-3-Carbonitriles as DYRK1A Inhibitors by Fragment-Based Drug Design.
Meine, Rosanna; Becker, Walter; Falke, Hannes; Preu, Lutz; Loaëc, Nadège; Meijer, Laurent; Kunick, Conrad
2018-01-24
Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a potential drug target because of its role in the development of Down syndrome and Alzheimer's disease. The selective DYRK1A inhibitor 10-iodo-11 H -indolo[3,2- c ]quinoline-6-carboxylic acid (KuFal194), a large, flat and lipophilic molecule, suffers from poor water solubility, limiting its use as chemical probe in cellular assays and animal models. Based on the structure of KuFal194, 7-chloro-1 H -indole-3-carbonitrile was selected as fragment template for the development of smaller and less lipophilic DYRK1A inhibitors. By modification of this fragment, a series of indole-3-carbonitriles was designed and evaluated as potential DYRK1A ligands by molecular docking studies. Synthesis and in vitro assays on DYRK1A and related protein kinases identified novel double-digit nanomolar inhibitors with submicromolar activity in cell culture assays.
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Utilization of Methacrylates and Polymer Matrices for the Synthesis of Ion Specific Resins
DOE Office of Scientific and Technical Information (OSTI.GOV)
Czerwinski, Kenneth
2013-10-29
Disposal, storage, and/or transmutation of actinides such as americium (Am) will require the development of specific separation schemes. Existing efforts focus on solvent extraction systems for achieving suitable separation of actinide from lanthanides. However, previous work has shown the feasibility of ion-imprinting polymer-based resins for use in ion-exchange-type separations with metal ion recognition. Phenolic-based resins have been shown to function well for Am-Eu separations, but these resins exhibited slow kinetics and difficulties in the imprinting process. This project addresses the need for new and innovative methods for the selective separation of actinides through novel ion-imprinted resins. The project team willmore » explore incorporation of metals into extended frameworks, including the possibility of 3D polymerized matrices that can serve as a solid-state template for specific resin preparation. For example, an anhydrous trivalent f-element chain can be formed directly from a metal carbonate, and methacrylic acid from water. From these simple coordination complexes, molecules of discrete size or shape can be formed via the utilization of coordinating ligands or by use of an anionic multi-ligand system incorporating methacrylate. Additionally, alkyl methyl methacrylates have been used successfully to create template nanospaces, which underscores their potential utility as 3D polymerized matrices. This evidence provides a unique route for the preparation of a specific metal ion template for the basis of ion-exchange separations. Such separations may prove to be excellent discriminators of metal ions, even between f-elements. Resins were prepared and evaluated for sorption behavior, column properties, and proton exchange capacity.« less
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Designing Templates for Interactive Tasks in CALL Tutorials.
ERIC Educational Resources Information Center
Ruhlmann, Felicitas
The development of templates for computer-assisted language learning (CALL) is discussed, based on experiences with primarily linear multimedia tutorial programs. Design of templates for multiple-choice questions and interactive tasks in a prototype module is described. Possibilities of enhancing interactivity by introducing problem-oriented…
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SMOG 2: A Versatile Software Package for Generating Structure-Based Models.
Noel, Jeffrey K; Levi, Mariana; Raghunathan, Mohit; Lammert, Heiko; Hayes, Ryan L; Onuchic, José N; Whitford, Paul C
2016-03-01
Molecular dynamics simulations with coarse-grained or simplified Hamiltonians have proven to be an effective means of capturing the functionally important long-time and large-length scale motions of proteins and RNAs. Originally developed in the context of protein folding, structure-based models (SBMs) have since been extended to probe a diverse range of biomolecular processes, spanning from protein and RNA folding to functional transitions in molecular machines. The hallmark feature of a structure-based model is that part, or all, of the potential energy function is defined by a known structure. Within this general class of models, there exist many possible variations in resolution and energetic composition. SMOG 2 is a downloadable software package that reads user-designated structural information and user-defined energy definitions, in order to produce the files necessary to use SBMs with high performance molecular dynamics packages: GROMACS and NAMD. SMOG 2 is bundled with XML-formatted template files that define commonly used SBMs, and it can process template files that are altered according to the needs of each user. This computational infrastructure also allows for experimental or bioinformatics-derived restraints or novel structural features to be included, e.g. novel ligands, prosthetic groups and post-translational/transcriptional modifications. The code and user guide can be downloaded at http://smog-server.org/smog2.
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Examining multi-component DNA-templated nanostructures as imaging agents
NASA Astrophysics Data System (ADS)
Jaganathan, Hamsa
2011-12-01
Magnetic resonance imaging (MRI) is the leading non-invasive tool for disease imaging and diagnosis. Although MRI exhibits high spatial resolution for anatomical features, the contrast resolution is low. Imaging agents serve as an aid to distinguish different types of tissues within images. Gadolinium chelates, which are considered first generation designs, can be toxic to health, while ultra-small, superparamagnetic nanoparticles (NPs) have low tissue-targeting efficiency and rapid bio-distribution, resulting to an inadequate detection of the MRI signal and enhancement of image contrast. In order to improve the utility of MRI agents, the challenge in composition and structure needs to be addressed. One-dimensional (1D), superparamagnetic nanostructures have been reported to enhance magnetic and in vivo properties and therefore has a potential to improve contrast enhancement in MRI images. In this dissertation, the structure of 1D, multi-component NP chains, scaffolded on DNA, were pre-clinically examined as potential MRI agents. First, research was focused on characterizing and understanding the mechanism of proton relaxation for DNA-templated NP chains using nuclear magnetic resonance (NMR) spectrometry. Proton relaxation and transverse relaxivity were higher in multi-component NP chains compared to disperse NPs, indicating the arrangement of NPs on a 1D structure improved proton relaxation sensitivity. Second, in vitro evaluation for potential issues in toxicity and contrast efficiency in tissue environments using a 3 Tesla clinical MRI scanner was performed. Cell uptake of DNA-templated NP chains was enhanced after encapsulating the nanostructure with layers of polyelectrolytes and targeting ligands. Compared to dispersed NPs, DNA-templated NP chains improved MRI contrast in both the epithelial basement membrane and colon cancer tumors scaffolds. The last part of the project was focused on developing a novel MRI agent that detects changes in DNA methylation levels. The findings from this dissertation suggest that the structural arrangement of NPs on DNA significantly influenced their function and utility as MRI agents.
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Callegari, Donatella; Pala, Daniele; Scalvini, Laura; Tognolini, Massimiliano; Incerti, Matteo; Rivara, Silvia; Mor, Marco; Lodola, Alessio
2015-09-17
The EphA2 receptor and its ephrin-A1 ligand form a key cell communication system, which has been found overexpressed in many cancer types and involved in tumor growth. Recent medicinal chemistry efforts have identified bile acid derivatives as low micromolar binders of the EphA2 receptor. However, these compounds suffer from poor physicochemical properties, hampering their use in vivo. The identification of compounds able to disrupt the EphA2-ephrin-A1 complex lacking the bile acid scaffold may lead to new pharmacological tools suitable for in vivo studies. To identify the most promising virtual screening (VS) protocol aimed at finding novel EphA2 antagonists, we investigated the ability of both ligand-based and structure-based approaches to retrieve known EphA2 antagonists from libraries of decoys with similar molecular properties. While ligand-based VSs were conducted using UniPR129 and ephrin-A1 ligand as reference structures, structure-based VSs were performed with Glide, using the X-ray structure of the EphA2 receptor/ephrin-A1 complex. A comparison of enrichment factors showed that ligand-based approaches outperformed the structure-based ones, suggesting ligand-based methods using the G-H loop of ephrin-A1 ligand as template as the most promising protocols to search for novel EphA2 antagonists.
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Saleh, Noureldin; Ibrahim, Passainte; Saladino, Giorgio; Gervasio, Francesco Luigi; Clark, Timothy
2017-05-22
A generally applicable metadynamics scheme for predicting the free energy profile of ligand binding to G-protein-coupled receptors (GPCRs) is described. A common and effective collective variable (CV) has been defined using the ideally placed and highly conserved Trp6.48 as a reference point for ligand-GPCR distance measurement and the common orientation of GPCRs in the cell membrane. Using this single CV together with well-tempered multiple-walker metadynamics with a funnel-like boundary allows an efficient exploration of the entire ligand binding path from the extracellular medium to the orthosteric binding site, including vestibule and intermediate sites. The protocol can be used with X-ray structures or high-quality homology models (based on a high-quality template and after thorough refinement) for the receptor and is universally applicable to agonists, antagonists, and partial and reverse agonists. The root-mean-square error (RMSE) in predicted binding free energies for 12 diverse ligands in five receptors (a total of 23 data points) is surprisingly small (less than 1 kcal mol -1 ). The RMSEs for simulations that use receptor X-ray structures and homology models are very similar.
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ForceGen 3D structure and conformer generation: from small lead-like molecules to macrocyclic drugs
NASA Astrophysics Data System (ADS)
Cleves, Ann E.; Jain, Ajay N.
2017-05-01
We introduce the ForceGen method for 3D structure generation and conformer elaboration of drug-like small molecules. ForceGen is novel, avoiding use of distance geometry, molecular templates, or simulation-oriented stochastic sampling. The method is primarily driven by the molecular force field, implemented using an extension of MMFF94s and a partial charge estimator based on electronegativity-equalization. The force field is coupled to algorithms for direct sampling of realistic physical movements made by small molecules. Results are presented on a standard benchmark from the Cambridge Crystallographic Database of 480 drug-like small molecules, including full structure generation from SMILES strings. Reproduction of protein-bound crystallographic ligand poses is demonstrated on four carefully curated data sets: the ConfGen Set (667 ligands), the PINC cross-docking benchmark (1062 ligands), a large set of macrocyclic ligands (182 total with typical ring sizes of 12-23 atoms), and a commonly used benchmark for evaluating macrocycle conformer generation (30 ligands total). Results compare favorably to alternative methods, and performance on macrocyclic compounds approaches that observed on non-macrocycles while yielding a roughly 100-fold speed improvement over alternative MD-based methods with comparable performance.
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Theory of nucleosome corkscrew sliding in the presence of synthetic DNA ligands.
Mohammad-Rafiee, Farshid; Kulić, Igor M; Schiessel, Helmut
2004-11-12
Histone octamers show a heat-induced mobility along DNA. Recent theoretical studies have established two mechanisms that are qualitatively and quantitatively compatible with in vitro experiments on nucleosome sliding: octamer repositioning through one-base-pair twist defects and through ten-base-pair bulge defects. A recent experiment demonstrated that the repositioning is strongly suppressed in the presence of minor-groove binding DNA ligands. In the present study, we give a quantitative theory for nucleosome repositioning in the presence of such ligands. We show that the experimentally observed octamer mobilities are consistent with the picture of bound ligands blocking the passage of twist defects through the nucleosome. This strongly supports the model of twist defects inducing a corkscrew motion of the nucleosome as the underlying mechanism of nucleosome sliding. We provide a theoretical estimate of the nucleosomal mobility without adjustable parameters, as a function of ligand concentration, binding affinity, binding site orientation, temperature and DNA anisotropy. Having this mobility in hand, we speculate on the interaction between a nucleosome and a transcribing RNA polymerase, and suggest a novel mechanism that might account for polymerase-induced nucleosome repositioning on short DNA templates.
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Structure of fluorescent metal clusters on a DNA template.
NASA Astrophysics Data System (ADS)
Vdovichev, A. A.; Sych, T. S.; Reveguk, Z. V.; Smirnova, A. A.; Maksimov, D. A.; Ramazanov, R. R.; Kononov, A. I.
2016-08-01
Luminescent metal clusters are a subject of growing interest in recent years due to their bright emission from visible to near infrared range. Detailed structure of the fluorescent complexes of Ag and other metal clusters with ligands still remains a challenging task. In this joint experimental and theoretical study we synthesized Ag-DNA complexes on a DNA oligonucleotide emitting in violet- green spectral range. The structure of DNA template was determined by means of various spectral measurements (CD, MS, XPS). Comparison of the experimental fluorescent excitation spectra and calculated absorption spectra for different QM/MM optimized structures allowed us to determine the detailed structure of the green cluster containing three silver atoms in the stem of the DNA hairpin structure stabilized by cytosine-Ag+-cytosine bonds.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Du Haijuan; Zunzhe Shu; Niu Yunyin, E-mail: niuyy@zzu.edu.cn
2012-06-15
Abstrct: Four novel organic-inorganic hybrid materials based on Mo-POMs and organic templates, namely [DEB] [{beta}-Mo{sub 8}O{sub 26}] [NH{sub 4}]{sub 2} (1), [BMIM] [{beta}-Mo{sub 8}O{sub 26}]{sub 0.5}{center_dot}H{sub 2}O (2), [BMIM] [1D-Mo{sub 8}O{sub 26}]{sub 0.5} (3) and {l_brace}3D-[Cu(DIE){sub 2}] [1D-Mo{sub 8}O{sub 26}]{sub 0.5}{r_brace}{sub {infinity}} (4) [DEB= 1,1 Prime -diethyl-4,4 Prime -bipyridinium, BMIM=1,1 Prime -bis(1-methylimidazolium)methylene, DIE=1,2-diimidazoloethane] have been hydrothermally synthesized and characterized by elemental analyses, IR spectroscopy, thermal gravimetric analysis(TGA) and single-crystal X-ray diffraction. Both compounds 1 and 2 are POMs-based supramolecular compounds consisted of independent [{beta}-Mo{sub 8}O{sub 26}]{sup 4-} anions and [DEB]{sup 2+} or [BMIM]{sup 2+} organic cations. Compound 3 is themore » first external template example of Mo-POMs-based supramolecular network incorporated with novel {sup 1}/{sub {infinity}}[{beta}-Mo{sub 8}O{sub 26}]{sup 4-} polymeric chains. Compound 4 is a rare supramolecular structure that contains octamolybdate {sup 1}/{sub {infinity}}[{beta}-Mo{sub 8}O{sub 26}]{sup 4-} polymeric chains interconnected via DIE ligands to form a 3D net. Moreover, it was indicated that these polyacid compounds had definite catalytic activities on the probe reaction of acetaldehyde oxidation to acetic acid with H{sub 2}O{sub 2}. - Graphical abstract: Four novel organic templated polyoxometalates comprising of 0D, 1D and 3D supramolecular frameworks together with the catalytic activities on the acetaldehyde oxidation to acetic acid were reported. Highlights: Using cation templated self-assembly four novel polyoxometalates were prepared. Compounds 1 and 2 consisted of independent [{beta}-Mo{sub 8}O{sub 26}]{sup 4-} anions and organic cations. Compound 3 is the first external template-assisted POMs with {sup 1}/{sub {infinity}}[{beta}-Mo{sub 8}O{sub 26}]{sup 4-} chain. Compound 4 is a rare 3D net containing {sup 1}/{sub {infinity}}[{beta}-Mo{sub 8}O{sub 26}]{sup 4-} 1D chain and DIE ligands. These compounds had definite catalytic activities on the acetaldehyde oxidation.« less
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G-LoSA for Prediction of Protein-Ligand Binding Sites and Structures.
Lee, Hui Sun; Im, Wonpil
2017-01-01
Recent advances in high-throughput structure determination and computational protein structure prediction have significantly enriched the universe of protein structure. However, there is still a large gap between the number of available protein structures and that of proteins with annotated function in high accuracy. Computational structure-based protein function prediction has emerged to reduce this knowledge gap. The identification of a ligand binding site and its structure is critical to the determination of a protein's molecular function. We present a computational methodology for predicting small molecule ligand binding site and ligand structure using G-LoSA, our protein local structure alignment and similarity measurement tool. All the computational procedures described here can be easily implemented using G-LoSA Toolkit, a package of standalone software programs and preprocessed PDB structure libraries. G-LoSA and G-LoSA Toolkit are freely available to academic users at http://compbio.lehigh.edu/GLoSA . We also illustrate a case study to show the potential of our template-based approach harnessing G-LoSA for protein function prediction.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Li, Na; Mu, Bao; Lv, Lei
Four new polyoxometalate(POM)–templated metal–organic frameworks based on flexible ligands, namely, [Cu{sub 6}(bip){sub 12}(PMo{sup VI}{sub 12}O{sub 40}){sub 2}(PMo{sup V}Mo{sup VI}{sub 11}O{sub 40}O{sub 2})]·8H{sub 2}O(1), [Cu{sup I}{sub 3}Cu{sup II}{sub 3}(bip){sub 12}(PMo{sup VI}{sub 12}O{sub 40}){sub 2}(PMo{sup V}{sub 12}O{sub 34})]·8H{sub 2}O(2), [Ni{sub 6}(bip){sub 12}(PMo{sup VI}{sub 12}O{sub 40})(PMo{sup VI}{sub 11}Mo{sup V}O{sub 40}){sub 2}]Cl·6H{sub 2}O(3), [Co{sup II}{sub 3}Co{sup III}{sub 2}(H{sub 2}bib){sub 2}(Hbib){sub 2}(PW{sub 9}O{sub 34}){sub 2}(H{sub 2}O){sub 6}]·6H{sub 2}O(4) (bip=1,3-bis(imidazolyl)propane, bib=1,4-bis(imidazolyl)butane) have been obtained under hydrothermal condition and characterized by single-crystal X-ray diffraction analyses, elemental analyses, and thermogravimetric (TG) analyses. The studies of single crystal X-ray indicate that compounds 1–3 crystallize in the trigonal space groupmore » P-3, and compound 4 crystallizes in the triclinic space group P-1. Compounds 1 and 3 represent 3D frameworks, and POMs as the guest molecules are incorporated into the cages which are composed of the ligands and metals, while compounds 2 and 4 show 3D frameworks by hydrogen bonds. This compounds provide new examples of host–guest compounds based on flexible bis(imidazole) ligands. In addition, the electrochemical property and the catalytic property of compound 1 have also been investigated. - Graphical abstract: Four inorganic–organic hybrid compounds based polyoxometalates (POMs) and flexible ligands, namely, have been obtained under hydrothermal conditions and characterized by single-crystal X-ray diffraction analyses, elemental analyses, IR spectra, and thermogravimetric (TG) analyses. Compounds 1–3 are new examples of host–guest compounds based on flexible bis(imidazole) ligands and POMs as the guest molecules are incorporated into the cages which are composed of the ligands and metals. - Highlights: • Polyoxometalate–templated metal–organic frameworks have been prepared. • POMs as the guest molecules are incorporated into the cages. • The cages are flexibility based on flexible bis(imidazole) ligands.« less
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Transdisciplinary Pedagogical Templates and Their Potential for Adaptive Reuse
ERIC Educational Resources Information Center
Dobozy, Eva; Dalziel, James
2016-01-01
This article explores the use and usefulness of carefully designed transdisciplinary pedagogical templates (TPTs) aligned to different learning theories. The TPTs are based on the Learning Design Framework outlined in the Larnaca Declaration (Dalziel et al. in this collection). The generation of pedagogical plans or templates is not new. However,…
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The Design of a Templated C++ Small Vector Class for Numerical Computing
NASA Technical Reports Server (NTRS)
Moran, Patrick J.
2000-01-01
We describe the design and implementation of a templated C++ class for vectors. The vector class is templated both for vector length and vector component type; the vector length is fixed at template instantiation time. The vector implementation is such that for a vector of N components of type T, the total number of bytes required by the vector is equal to N * size of (T), where size of is the built-in C operator. The property of having a size no bigger than that required by the components themselves is key in many numerical computing applications, where one may allocate very large arrays of small, fixed-length vectors. In addition to the design trade-offs motivating our fixed-length vector design choice, we review some of the C++ template features essential to an efficient, succinct implementation. In particular, we highlight some of the standard C++ features, such as partial template specialization, that are not supported by all compilers currently. This report provides an inventory listing the relevant support currently provided by some key compilers, as well as test code one can use to verify compiler capabilities.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Baum, Bernhard; Lecker, Laura S. M.; Zoltner, Martin
Three crystal structures of recombinant P. aeruginosa FabF are reported: the apoenzyme, an active-site mutant and a complex with a fragment of a natural product inhibitor. The characterization provides reagents and new information to support antibacterial drug discovery. Bacterial infections remain a serious health concern, in particular causing life-threatening infections of hospitalized and immunocompromised patients. The situation is exacerbated by the rise in antibacterial drug resistance, and new treatments are urgently sought. In this endeavour, accurate structures of molecular targets can support early-stage drug discovery. Here, crystal structures, in three distinct forms, of recombinant Pseudomonas aeruginosa β-ketoacyl-(acyl-carrier-protein) synthase II (FabF)more » are presented. This enzyme, which is involved in fatty-acid biosynthesis, has been validated by genetic and chemical means as an antibiotic target in Gram-positive bacteria and represents a potential target in Gram-negative bacteria. The structures of apo FabF, of a C164Q mutant in which the binding site is altered to resemble the substrate-bound state and of a complex with 3-(benzoylamino)-2-hydroxybenzoic acid are reported. This compound mimics aspects of a known natural product inhibitor, platensimycin, and surprisingly was observed binding outside the active site, interacting with a symmetry-related molecule. An unusual feature is a completely buried potassium-binding site that was identified in all three structures. Comparisons suggest that this may represent a conserved structural feature of FabF relevant to fold stability. The new structures provide templates for structure-based ligand design and, together with the protocols and reagents, may underpin a target-based drug-discovery project for urgently needed antibacterials.« less
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Developing SABRE as an analytical tool in NMR
NASA Astrophysics Data System (ADS)
Lloyd, Lyrelle Stacey
Work presented in this thesis centres around the application of the new hyperpolarisation technique, SABRE, within nuclear magnetic resonance spectroscopy, focusing on optimisation of the technique to characterise small organic molecules. While pyridine was employed as a model substrate, studies on a range of molecules are investigated including substituted pyridines, quinolines, thiazoles and indoles are detailed. Initial investigations explored how the properties of the SABRE catalyst effect the extent of polarisation transfer exhibited. The most important of these properties proved to be the rate constants for loss of pyridine and hydrides as these define the contact time of pyridine with the parahydrogen derived hydride ligands in the metal template. The effect of changing the temperature, solvent or concentration of substrate or catalyst are rationalised. For instance, the catalyst ICy(a) exhibits relatively slow ligand exchange rates and increasing the temperature during hyperpolarisation increases the observed signal enhancements. These studies have revealed a second polarisation transfer template can be used with SABRE in which two substrate molecules are bound. This allows the possibility of investigation of larger substrates which might otherwise be too sterically encumbered to bind. Another significant advance relates to the first demonstration that SABRE can be used in conjunction with an automated system designed with Bruker allowing the acquisition of scan averaged, phase cycled and traditional 2D spectra. The system also allowed investigations into the effect of the polarisation transfer field and application of that knowledge to collect single-scan 13C data for characterisation. The successful acquisition of 1H NOESY, 1H-1H COSY, 1H-13C 2D and ultrafast 1H-1H COSY NMR sequences is detailed for a 10 mM concentration sample, with 1H data collected for a 1 mM sample. A range of studies which aim to demonstrate the applicability of SABRE to the characterisation of small molecules and pharmaceuticals have been conducted.
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Synthesis of [Fe(Leq)(Lax)] n coordination polymer nanoparticles using blockcopolymer micelles.
Göbel, Christoph; Klimm, Ottokar; Puchtler, Florian; Rosenfeldt, Sabine; Förster, Stephan; Weber, Birgit
2017-01-01
Spin-crossover compounds are a class of materials that can change their spin state from high spin (HS) to low spin (LS) by external stimuli such as light, pressure or temperature. Applications demand compounds with defined properties concerning the size and switchability that are maintained when the compound is integrated into composite materials. Here, we report the synthesis of [Fe(L eq )(L ax )] n coordination polymer (CP) nanoparticles using self-assembled polystyrene- block -poly(4-vinylpyridine) (PS- b -P4VP) block copolymer (BCP) micelles as template. Variation of the solvent (THF and toluene) and the rigidity of the axial ligand L ax (L ax = 1,2-di(pyridin-4-yl)ethane) (bpea), trans -1,2-di(pyridin-4-yl)ethene (bpee), and 1,2-di(pyridin-4-yl)ethyne) (bpey); L eq = 1,2-phenylenebis(iminomethylidyne)-bis(2,4-pentanedionato)(2-)) allowed the determination of the preconditions for the selective formation of nanoparticles. A low solubility of the CP in the used solvent and a high stability of the Fe-L bond with regard to ligand exchange are necessary for the formation of composite nanoparticles where the BCP micelle is filled with the CP, as in the case of the [FeL eq (bpey)] n @BCP. Otherwise, in the case of more flexible ligands or ligands that lead to high spin complexes, the formation of microcrystals next to the CP-BCP nanoparticles is observed above a certain concentration of [Fe(L eq )(L ax )] n . The core of the nanoparticles is about 45 nm in diameter due to the templating effect of the BCP micelle, independent of the used iron complex and [Fe(L eq )(L ax )] n concentration. The spin-crossover properties of the composite material are similar to those of the bulk for FeL eq (bpea)] n @BCP while pronounced differences are observed in the case of [FeL eq (bpey)] n @BCP nanoparticles.
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Benzoate-Induced High-Nuclearity Silver Thiolate Clusters.
Su, Yan-Min; Liu, Wei; Wang, Zhi; Wang, Shu-Ao; Li, Yan-An; Yu, Fei; Zhao, Quan-Qin; Wang, Xing-Po; Tung, Chen-Ho; Sun, Di
2018-04-03
Compared with the well-known anion-templated effects in shaping silver thiolate clusters, the influence from the organic ligands in the outer shell is still poorly understood. Herein, three new benzoate-functionalized high-nuclearity silver(I) thiolate clusters are isolated and characterized for the first time in the presence of diverse anion templates such as S 2- , α-[Mo 5 O 18 ] 6- , and MoO 4 2- . Single-crystal X-ray analysis reveals that the nuclearities of the three silver clusters (SD/Ag28, SD/Ag29, SD/Ag30) vary from 32 to 38 to 78 with co-capped tBuS - and benzoate ligands on the surface. SD/Ag28 is a turtle-like cluster comprising a Ag 29 shell caging a Ag 3 S 3 trigon in the center, whereas SD/Ag29 is a prolate Ag 38 sphere templated by the α-[Mo 5 O 18 ] 6- anion. Upon changing from benzoate to methoxyl-substituted benzoate, SD/Ag30 is isolated as a very complicated core-shell spherical cluster composed of a Ag 57 shell and a vase-like Ag 21 S 13 core. Four MoO 4 2- anions are arranged in a supertetrahedron and located in the interstice between the core and shell. Introduction of the bulky benzoate changes elaborately the nuclearity and arrangements of silver polygons on the shell of silver clusters, which is exemplified by comparing SD/Ag28 and a known similar silver thiolate cluster. The three new clusters emit luminescence in the near-infrared (NIR) region and show different thermochromic luminescence properties. This work presents a flexible approach to synthetic studies of high-nuclearity silver clusters decorated by different benzoates, and structural modulations are also achieved. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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RADER: a RApid DEcoy Retriever to facilitate decoy based assessment of virtual screening.
Wang, Ling; Pang, Xiaoqian; Li, Yecheng; Zhang, Ziying; Tan, Wen
2017-04-15
Evaluation of the capacity for separating actives from challenging decoys is a crucial metric of performance related to molecular docking or a virtual screening workflow. The Directory of Useful Decoys (DUD) and its enhanced version (DUD-E) provide a benchmark for molecular docking, although they only contain a limited set of decoys for limited targets. DecoyFinder was released to compensate the limitations of DUD or DUD-E for building target-specific decoy sets. However, desirable query template design, generation of multiple decoy sets of similar quality, and computational speed remain bottlenecks, particularly when the numbers of queried actives and retrieved decoys increases to hundreds or more. Here, we developed a program suite called RApid DEcoy Retriever (RADER) to facilitate the decoy-based assessment of virtual screening. This program adopts a novel database-management regime that supports rapid and large-scale retrieval of decoys, enables high portability of databases, and provides multifaceted options for designing initial query templates from a large number of active ligands and generating subtle decoy sets. RADER provides two operational modes: as a command-line tool and on a web server. Validation of the performance and efficiency of RADER was also conducted and is described. RADER web server and a local version are freely available at http://rcidm.org/rader/ . lingwang@scut.edu.cn or went@scut.edu.cn . Supplementary data are available at Bioinformatics online. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com
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Miszta, Przemyslaw; Pasznik, Pawel; Jakowiecki, Jakub; Sztyler, Agnieszka; Latek, Dorota; Filipek, Slawomir
2018-05-21
Due to the involvement of G protein-coupled receptors (GPCRs) in most of the physiological and pathological processes in humans they have been attracting a lot of attention from pharmaceutical industry as well as from scientific community. Therefore, the need for new, high quality structures of GPCRs is enormous. The updated homology modeling service GPCRM (http://gpcrm.biomodellab.eu/) meets those expectations by greatly reducing the execution time of submissions (from days to hours/minutes) with nearly the same average quality of obtained models. Additionally, due to three different scoring functions (Rosetta, Rosetta-MP, BCL::Score) it is possible to select accurate models for the required purposes: the structure of the binding site, the transmembrane domain or the overall shape of the receptor. Currently, no other web service for GPCR modeling provides this possibility. GPCRM is continually upgraded in a semi-automatic way and the number of template structures has increased from 20 in 2013 to over 90 including structures the same receptor with different ligands which can influence the structure not only in the on/off manner. Two types of protein viewers can be used for visual inspection of obtained models. The extended sortable tables with available templates provide links to external databases and display ligand-receptor interactions in visual form.
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Ligand exchange and MIP-based paraoxon memories onto QCM sensor
NASA Astrophysics Data System (ADS)
Birlik Özkütük, Ebru; Emir Diltemiz, Sibel; Özalp, Elif; Uzun, Lokman; Ersöz, Arzu
2015-04-01
In this study, we have aimed to prepare quartz crystal microbalance (QCM) sensor using paraoxon-imprinted particles. Firstly, methacryloyl antipyrine (MAAP)-based metal-chelate-coordinated pre-complex has been prepared and used for paraoxon templation. Then, paraoxon-imprinted nanofilms were formed on QCM sensor after modification of the gold surfaces with allyl mercaptan. By this way, specific and selective memories, which depend on metal-chelate interactions between Eu(III) ions and template, for paraoxon molecules have been obtained on the electrode surface. QCM sensor has characterized using AFM and ellipsometer. The detection limit and the affinity constant have found to be 0.09 μM and 5.71 × 103 M-1 for MAAP-Eu paraoxon-based nanofilm, respectively. The specificity of the QCM sensor has shown using parathion as a competitor molecule.
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Mechanistic Study of Human Glucose Transport Mediated by GLUT1.
Fu, Xuegang; Zhang, Gang; Liu, Ran; Wei, Jing; Zhang-Negrerie, Daisy; Jian, Xiaodong; Gao, Qingzhi
2016-03-28
The glucose transporter 1 (GLUT1) belongs to the major facilitator superfamily (MFS) and is responsible for the constant uptake of glucose. However, the molecular mechanism of sugar transport remains obscure. In this study, homology modeling and molecular dynamics (MD) simulations in lipid bilayers were performed to investigate the combination of the alternate and multisite transport mechanism of glucose with GLUT1 in atomic detail. To explore the substrate recognition mechanism, the outward-open state human GLUT1 homology model was generated based on the template of xylose transporter XylE (PDB ID: 4GBZ), which shares up to 29% sequence identity and 49% similarity with GLUT1. Through the MD simulation study of glucose across lipid bilayer with both the outward-open GLUT1 and the GLUT1 inward-open crystal structure, we investigated six different conformational states and identified four key binding sites in both exofacial and endofacial loops that are essential for glucose recognition and transport. The study further revealed that four flexible gates consisting of W65/Y292/Y293-M420/TM10b-W388 might play important roles in the transport cycle. The study showed that some side chains close to the central ligand binding site underwent larger position changes. These conformational interchanges formed gated networks within an S-shaped central channel that permitted staged ligand diffusion across the transporter. This study provides new inroads for the understanding of GLUT1 ligand recognition paradigm and configurational features which are important for molecular, structural, and physiological research of the MFS members, especially for GLUT1-targeted drug design and discovery.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Y Li; Q Wang; R Mariuzza
2011-12-31
Natural killer (NK) cells are lymphocytes of the innate immune system that participate in the elimination of tumor cells. In humans, the activating natural cytotoxicity receptors (NCRs) NKp30, NKp44, and NKp46 play a major role in NK cell-mediated tumor cell lysis. NKp30 recognizes B7-H6, a member of the B7 family which is expressed on tumor, but not healthy, cells. To understand the basis for tumor surveillance by NCRs, we determined the structure of NKp30, a member of the CD28 family which includes CTLA-4 and PD-1, in complex with B7-H6. The overall organization of the NKp30-B7-H6-activating complex differs considerably from thosemore » of the CTLA-4-B7 and PD-1-PD-L T cell inhibitory complexes. Whereas CTLA-4 and PD-1 use only the front {beta}-sheet of their Ig-like domain to bind ligands, NKp30 uses both front and back {beta}-sheets, resulting in engagement of B7-H6 via the side, as well as face, of the {beta}-sandwich. Moreover, B7-H6 contacts NKp30 through the complementarity-determining region (CDR) - like loops of its V-like domain in an antibody-like interaction that is not observed for B7 or PD-L. This first structure of an NCR bound to ligand provides a template for designing molecules to stimulate NKp30-mediated cytolytic activity for tumor immunotherapy.« less
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NASA Astrophysics Data System (ADS)
da Silva Figueiredo Celestino Gomes, Priscila; Da Silva, Franck; Bret, Guillaume; Rognan, Didier
2018-01-01
A novel docking challenge has been set by the Drug Design Data Resource (D3R) in order to predict the pose and affinity ranking of a set of Farnesoid X receptor (FXR) agonists, prior to the public release of their bound X-ray structures and potencies. In a first phase, 36 agonists were docked to 26 Protein Data Bank (PDB) structures of the FXR receptor, and next rescored using the in-house developed GRIM method. GRIM aligns protein-ligand interaction patterns of docked poses to those of available PDB templates for the target protein, and rescore poses by a graph matching method. In agreement with results obtained during the previous 2015 docking challenge, we clearly show that GRIM rescoring improves the overall quality of top-ranked poses by prioritizing interaction patterns already visited in the PDB. Importantly, this challenge enables us to refine the applicability domain of the method by better defining the conditions of its success. We notably show that rescoring apolar ligands in hydrophobic pockets leads to frequent GRIM failures. In the second phase, 102 FXR agonists were ranked by decreasing affinity according to the Gibbs free energy of the corresponding GRIM-selected poses, computed by the HYDE scoring function. Interestingly, this fast and simple rescoring scheme provided the third most accurate ranking method among 57 contributions. Although the obtained ranking is still unsuitable for hit to lead optimization, the GRIM-HYDE scoring scheme is accurate and fast enough to post-process virtual screening data.
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Ballet, Steven; Salvadori, Severo; Trapella, Claudio; Bryant, Sharon D; Jinsmaa, Yunden; Lazarus, Lawrence H; Negri, Lucia; Giannini, Elisa; Lattanzi, Roberta; Tourwé, Dirk; Balboni, Gianfranco
2006-06-29
The Aba-Gly scaffold, incorporated into Dmt-Tic ligands (H-Dmt-Tic-Gly-NH-CH2-Ph, H-Dmt-Tic-Gly-NH-Ph, H-Dmt-Tic-NH-CH2-Bid), exhibited mixed micro/delta or delta opioid receptor activities with micro agonism. Substitution of Tic by Aba-Gly coupled to -NH-CH2-Ph (1), -NH-Ph (2), or -Bid (Bid=1H-benzimidazole-2-yl) (3) shifted affinity (Ki(micro)=0.46, 1.48, and 19.9 nM, respectively), selectivity, and bioactivity to micro-opioid receptors. These compounds represent templates for a new class of lead opioid agonists that are easily synthesized and suitable for therapeutic pain relief.
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Feasibility study of patient-specific surgical templates for the fixation of pedicle screws.
Salako, F; Aubin, C-E; Fortin, C; Labelle, H
2002-01-01
Surgery for scoliosis, as well as other posterior spinal surgeries, frequently uses pedicle screws to fix an instrumentation on the spine. Misplacement of a screw can lead to intra- and post-operative complications. The objective of this study is to design patient-specific surgical templates to guide the drilling operation. From the CT-scan of a vertebra, the optimal drilling direction and limit angles are computed from an inverse projection of the pedicle limits. The first template design uses a surface-to-surface registration method and was constructed in a CAD system by subtracting the vertebra from a rectangular prism and a cylinder with the optimal orientation. This template and the vertebra were built using rapid prototyping. The second design uses a point-to-surface registration method and has 6 adjustable screws to adjust the orientation and length of the drilling support device. A mechanism was designed to hold it in place on the spinal process. A virtual prototype was build with CATIA software. During the operation, the surgeon places either template on patient's vertebra until a perfect match is obtained before drilling. The second design seems better than the first one because it can be reused on different vertebra and is less sensible to registration errors. The next step is to build the second design and make experimental and simulations tests to evaluate the benefits of this template during a scoliosis operation.
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Discovering New Acetylcholinesterase Inhibitors by Mining the Buzhongyiqi Decoction Recipe Data.
Cui, Lu; Wang, Yu; Liu, Zhihong; Chen, Hongzhuan; Wang, Hao; Zhou, Xinxin; Xu, Jun
2015-11-23
Myasthenia gravis (MG) is a neuromuscular disease that is conventionally treated with acetylcholinesterase (AChE) inhibitors, which may not fully remove the symptom for many reasons. When AChE inhibitors do not work, Chinese patients turn to Chinese medicine, such as the Buzhongyiqi decoction (BD), to treat MG. By elucidating the relations between the herbs of the Buzhongyiqi decoction recipe and AChE inhibitors with structure-based and ligand-based drug design methods and chemoinformatics approaches, we have found the key active components of BD. Using these key active components as templates, we have discovered five new AChE inhibitors through virtual screening of a commercial compound library. The new AChE inhibitors have been confirmed with Ellman assays. This study demonstrates that lead identification can be inspired by elucidating Chinese medicine. Since BD is a mixture, further studies against other drug targets are needed.
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Journal of Chemical Education: Software.
ERIC Educational Resources Information Center
Journal of Chemical Education, 1989
1989-01-01
"Spreadsheets in Physical Chemistry" contains reviewed and classroom tested Lotus 1-2-3 and SuperCalc IV templates and handouts designed for use in physical chemistry courses. The 21 templates keyed to Atkins' physical chemistry textbook, the 7 numerical methods templates, and the 10 simulation templates are discussed. (MVL)
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Muench, Falk; Schaefer, Sandra; Hagelüken, Lorenz; Molina-Luna, Leopoldo; Duerrschnabel, Michael; Kleebe, Hans-Joachim; Brötz, Joachim; Vaskevich, Alexander; Rubinstein, Israel; Ensinger, Wolfgang
2017-09-13
Metal nanowires (NWs) represent a prominent nanomaterial class, the interest in which is fueled by their tunable properties as well as their excellent performance in, for example, sensing, catalysis, and plasmonics. Synthetic approaches to obtain metal NWs mostly produce colloids or rely on templates. Integrating such nanowires into devices necessitates additional fabrication steps, such as template removal, nanostructure purification, or attachment. Here, we describe the development of a facile electroless plating protocol for the direct deposition of gold nanowire films, requiring neither templates nor complex instrumentation. The method is general, producing three-dimensional nanowire structures on substrates of varying shape and composition, with different seed types. The aqueous plating bath is prepared by ligand exchange and partial reduction of tetrachloroauric acid in the presence of 4-dimethylaminopyridine and formaldehyde. Gold deposition proceeds by nucleation of new grains on existing nanostructure tips and thus selectively produces curvy, polycrystalline nanowires of high aspect ratio. The nanofabrication potential of this method is demonstrated by producing a sensor electrode, whose performance is comparable to that of known nanostructures and discussed in terms of the catalyst architecture. Due to its flexibility and simplicity, shape-selective electroless plating is a promising new tool for functionalizing surfaces with anisotropic metal nanostructures.
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GPCR-ModSim: A comprehensive web based solution for modeling G-protein coupled receptors
Esguerra, Mauricio; Siretskiy, Alexey; Bello, Xabier; Sallander, Jessica; Gutiérrez-de-Terán, Hugo
2016-01-01
GPCR-ModSim (http://open.gpcr-modsim.org) is a centralized and easy to use service dedicated to the structural modeling of G-protein Coupled Receptors (GPCRs). 3D molecular models can be generated from amino acid sequence by homology-modeling techniques, considering different receptor conformations. GPCR-ModSim includes a membrane insertion and molecular dynamics (MD) equilibration protocol, which can be used to refine the generated model or any GPCR structure uploaded to the server, including if desired non-protein elements such as orthosteric or allosteric ligands, structural waters or ions. We herein revise the main characteristics of GPCR-ModSim and present new functionalities. The templates used for homology modeling have been updated considering the latest structural data, with separate profile structural alignments built for inactive, partially-active and active groups of templates. We have also added the possibility to perform multiple-template homology modeling in a unique and flexible way. Finally, our new MD protocol considers a series of distance restraints derived from a recently identified conserved network of helical contacts, allowing for a smoother refinement of the generated models which is particularly advised when there is low homology to the available templates. GPCR- ModSim has been tested on the GPCR Dock 2013 competition with satisfactory results. PMID:27166369
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Pioszak, Augen A.; Parker, Naomi R.; Gardella, Thomas J.
2009-12-01
Parathyroid hormone (PTH) and PTH-related protein (PTHrP) are two related peptides that control calcium/phosphate homeostasis and bone development, respectively, through activation of the PTH/PTHrP receptor (PTH1R), a class B G protein-coupled receptor. Both peptides hold clinical interest for their capacities to stimulate bone formation. PTH and PTHrP display different selectivity for two distinct PTH1R conformations, but how their binding to the receptor differs is unclear. The high resolution crystal structure of PTHrP bound to the extracellular domain (ECD) of PTH1R reveals that PTHrP binds as an amphipathic {alpha}-helix to the same hydrophobic groove in the ECD as occupied by PTH,more » but in contrast to a straight, continuous PTH helix, the PTHrP helix is gently curved and C-terminally 'unwound.' The receptor accommodates the altered binding modes by shifting the side chain conformations of two residues within the binding groove: Leu-41 and Ile-115, the former acting as a rotamer toggle switch to accommodate PTH/PTHrP sequence divergence, and the latter adapting to the PTHrP curvature. Binding studies performed with PTH/PTHrP hybrid ligands having reciprocal exchanges of residues involved in different contacts confirmed functional consequences for the altered interactions and enabled the design of altered PTH and PTHrP peptides that adopt the ECD-binding mode of the opposite peptide. Hybrid peptides that bound the ECD poorly were selective for the G protein-coupled PTH1R conformation. These results establish a molecular model for better understanding of how two biologically distinct ligands can act through a single receptor and provide a template for designing better PTH/PTHrP therapeutics.« less
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Tala, Srinivasa R; Singh, Anamika; Lensing, Cody J; Schnell, Sathya M; Freeman, Katie T; Rocca, James R; Haskell-Luevano, Carrie
2018-05-16
The melanocortin system is involved in the regulation of complex physiological functions, including energy and weight homeostasis, feeding behavior, inflammation, sexual function, pigmentation, and exocrine gland function. The five melanocortin receptors that belong to the superfamily of G protein-coupled receptors (GPCRs) are regulated by endogenously expressed agonists and antagonists. The aim of this study was to explore the potential of replacing the disulfide bridge in chimeric AGRP-melanocortin peptide Tyr-c[Cys-His-d-Phe-Arg-Trp-Asn-Ala-Phe-Cys]-Tyr-NH 2 (1) with 1,2,3-triazole moieties. A series of 1,2,3-triazole-bridged peptidomimetics were designed, synthesized, and pharmacologically evaluated at the mouse melanocortin receptors. The ligands possessed nanomolar to micromolar agonist cAMP signaling potency. A key finding was that the disulfide bond in peptide 1 can be replaced with the monotriazole ring with minimal effect on the functional activity at the melanocortin receptors. The 1,5-disubstituted triazole-bridged peptide 6 showed equipotent functional activity at the mMC3R and modest 5-fold decreased agonist potency at the mMC4R compared to those of 1. Interestingly, the 1,4- and 1,5-disubstituted isomers of the triazole ring resulted in different selectivities at the receptor subtypes, indicating subtle structural features that may be exploited in the generation of selective melanocortin ligands. Introducing cyclic and acyclic bis-triazole moieties into chimeric AGRP template 1 generally decreased agonist activity. These results will be useful for the further design of neuronal chemical probes for the melanocortin receptors as well as in other receptor systems.
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Takemoto, Mitsuru; Fujibayashi, Shunsuke; Ota, Eigo; Otsuki, Bungo; Kimura, Hiroaki; Sakamoto, Takeshi; Kawai, Toshiyuki; Futami, Tohru; Sasaki, Kiyoyuki; Matsushita, Tomiharu; Nakamura, Takashi; Neo, Masashi; Matsuda, Shuich
2016-06-01
Image-based navigational patient-specific templates (PSTs) for pedicle screw (PS) placement have been described. With recent advances in three-dimensional computer-aided designs and additive manufacturing technology, various PST designs have been reported, although the template designs were not optimized. We have developed a novel PST design that reduces the contact area without sacrificing stability. It avoids susceptibility to intervening soft tissue, template geometric inaccuracy, and difficulty during template fitting. Fourteen candidate locations on the posterior aspect of the vertebra were evaluated. Among them, locations that had high reproducibility on computed tomography (CT) images and facilitated accurate PS placement were selected for the final PST design. An additive manufacturing machine (EOSINT M270) fabricated the PSTs using commercially pure titanium powder. For the clinical study, 36 scoliosis patients and 4 patients with ossification of the posterior longitudinal ligament (OPLL) were treated with thoracic PSs using our newly developed PSTs. We intraoperatively and postoperatively evaluated the accuracy of the PS hole created by the PST. Based on the segmentation reproducibility and stability analyses, we selected seven small, round contact points for our PST: bilateral superior and inferior points on the transverse process base, bilateral inferior points on the laminar, and a superior point on the spinous process. Clinically, the success rates of PS placement using this PST design were 98.6 % (414/420) for scoliosis patients and 100 % (46/46) for OPLL patients. This study provides a useful design concept for the development and introduction of patient-specific navigational templates for placing PSs.
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EMS technology assessment template
DOT National Transportation Integrated Search
2008-01-01
This technology assessment template is designed to evaluate information technology and EMS devices that provide data about patients, evaluation-oriented clinical patient information, or decision support tools. The template may also be used by consume...
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Use of rapid prototyping drill template for the expansive open door laminoplasty: A cadaveric study.
Rong, Xin; Wang, Beiyu; Chen, Hua; Ding, Chen; Deng, Yuxiao; Ma, Lipeng; Ma, Yanzhao; Liu, Hao
2016-11-01
Trough preparation is a technically demanding yet critical procedure for successful expansive open door laminoplasty (EOLP), requiring both proper position and appropriate bone removal. We aimed to use the specific rapid prototyping drill template to achieve such requirement. The 3D model of the cadaveric cervical spine was reconstructed using the Mimics 17.0 and Geomagic Studio 12.0 software. The drilling template was designed in the 3-Matic software. The trough position was simulated at the medial margin of the facet joint. Two holders were designed on both sides. On the open side, the holder would just allow the drill penetrate the ventral cortex of the lamina. On the hinge side, the holder was designed to keep the ventral cortex of the lamina intact. One orthopedic resident performed the surgery using the rapid prototyping drill template on four cadavers (template group). A control group of four cadavers were operated upon without the use of the template. The deviation of the final trough position from the simulated trough position was 0.18mm±0.51mm in the template group. All the troughs in the template group and 40% of the troughs in the control group were at the medial side of the facet joint. The complete hinge fracture rate was 5% in the template group, significantly lower than that (55%) in the control group (P=0.01). The rapid prototyping drill template could help the surgeon accomplish proper trough position and appropriate bone removal in EOLP on the cadaveric cervical spine. Copyright © 2016 Elsevier B.V. All rights reserved.
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NASA Astrophysics Data System (ADS)
Birrento, Monica L.; Bryan, Tracy M.; Samosorn, Siritron; Beck, Jennifer L.
2015-07-01
Electrospray ionization mass spectrometry (ESI-MS) conditions were optimized for simultaneous observation of a bimolecular qDNA and a Watson-Crick base-paired duplex DNA/RNA hybrid. The DNA sequence used was telomeric DNA, and the RNA contained the template for telomerase-mediated telomeric DNA synthesis. Addition of RNA to the quadruplex DNA (qDNA) resulted in formation of the duplex DNA/RNA hybrid. Melting profiles obtained using circular dichroism spectroscopy confirmed that the DNA/RNA hybrid exhibited greater thermal stability than the bimolecular qDNA in solution. Binding of a 13-substituted berberine ( 1) derivative to the bimolecular qDNA stabilized its structure as evidenced by an increase in its stability in the mass spectrometer, and an increase in its circular dichroism (CD) melting temperature of 10°C. The DNA/RNA hybrid did not bind the ligand extensively and its thermal stability was unchanged in the presence of ( 1). The qDNA-ligand complex resisted unfolding in the presence of excess RNA, limiting the formation of the DNA/RNA hybrid. Previously, it has been proposed that DNA secondary structures, such as qDNA, may be involved in the telomerase mechanism. DNA/RNA hybrid structures occur at the active site of telomerase. The results presented in the current work show that if telomeric DNA was folded into a qDNA structure, it is possible for a DNA/RNA hybrid to form as is required during template alignment. The discrimination of ligand ( 1) for binding to the bimolecular qDNA over the DNA/RNA hybrid positions it as a useful compound for probing the role(s), if any, of antiparallel qDNA in the telomerase mechanism.
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Detection of Waterborne Viruses Using High Affinity Molecularly Imprinted Polymers.
Altintas, Zeynep; Gittens, Micah; Guerreiro, Antonio; Thompson, Katy-Anne; Walker, Jimmy; Piletsky, Sergey; Tothill, Ibtisam E
2015-07-07
Molecularly imprinted polymers (MIPs) are artificial receptor ligands which can recognize and specifically bind to a target molecule. They are more resistant to chemical and biological damage and inactivation than antibodies. Therefore, target specific-MIP nanoparticles are aimed to develop and implemented to biosensors for the detection of biological toxic agents such as viruses, bacteria, and fungi toxins that cause many diseases and death due to the environmental contamination. For the first time, a molecularly imprinted polymer (MIP) targeting the bacteriophage MS2 as the template was investigated using a novel solid-phase synthesis method to obtain the artificial affinity ligand for the detection and removal of waterborne viruses through optical-based sensors. A high affinity between the artificial ligand and the target was found, and a regenerative MIP-based virus detection assay was successfully developed using a new surface plasmon resonance (SPR)-biosensor which provides an alternative technology for the specific detection and removal of waterborne viruses that lead to high disease and death rates all over the world.
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Savoy, April; Patel, Himalaya; Flanagan, Mindy E; Weiner, Michael; Russ, Alissa L
2017-08-01
We assessed the usability of consultation order templates and identified problems to prioritize in design efforts for improving referral communication. With a sample of 26 consultation order templates, three evaluators performed a usability heuristic evaluation. The evaluation used 14 domain-independent heuristics and the following three supplemental references: 1 new domain-specific heuristic, 6 usability goals, and coded clinicians' statements regarding ease of use for 10 sampled templates. Evaluators found 201 violations, a mean of 7.7 violations per template. Minor violations outnumbered major violations almost twofold, 115 (57%) to 62 (31%). Approximately 68% of violations were linked to 5 heuristics: aesthetic and minimalist design (17%), error prevention (16%), consistency and standards (14%), recognition rather than recall (11%), and meet referrers' information needs (10%). Severe violations were attributed mostly to meet referrers' information needs and recognition rather than recall. Recorded violations yielded potential negative consequences for efficiency, effectiveness, safety, learnability, and utility. Evaluators and clinicians demonstrated 80% agreement in usability assessment. Based on frequency and severity of usability heuristic violations, the consultation order templates reviewed may impede clinical efficiency and risk patient safety. Results support the following design considerations: communicate consultants' requirements, facilitate information seeking, and support communication. While the most frequent heuristic violations involved interaction design and presentation, the most severe violations lacked information desired by referring clinicians. Violations related to templates' inability to support referring clinicians' information needs had the greatest potential negative impact on efficiency and safety usability goals. Heuristics should be prioritized in future design efforts.
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Lepage, Mathieu L; Schneider, Jérémy P; Bodlenner, Anne; Compain, Philippe
2015-11-06
A modular strategy has been developed to access a diversity of cyclic and acyclic oligosaccharide analogues designed as prefunctionalized scaffolds for the synthesis of multivalent ligands. This convergent approach is based on bifunctional sugar building blocks with two temporarily masked functionalities that can be orthogonally activated to perform Cu(I)-catalyzed azide-alkyne cycloaddition reactions (CuAAC). The reducing end is activated as a glycosyl azide and masked as a 1,6-anhydro sugar, while the nonreducing end is activated as a free alkyne and masked as a triethylsilyl-alkyne. Following a cyclooligomerization approach, the first examples of close analogues of cyclodextrins composed of d-glucose residues and triazole units bound together through α-(1,4) linkages were obtained. The cycloglucopyranoside analogue containing four sugar units was used as a template to prepare multivalent systems displaying a protected d-mannose derivative or an iminosugar by way of CuAAC. On the other hand, the modular approach led to acyclic alkyne-functionalized scaffolds of a controlled size that were used to synthesize multivalent iminosugars.
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Formation of target-specific binding sites in enzymes: solid-phase molecular imprinting of HRP
NASA Astrophysics Data System (ADS)
Czulak, J.; Guerreiro, A.; Metran, K.; Canfarotta, F.; Goddard, A.; Cowan, R. H.; Trochimczuk, A. W.; Piletsky, S.
2016-05-01
Here we introduce a new concept for synthesising molecularly imprinted nanoparticles by using proteins as macro-functional monomers. For a proof-of-concept, a model enzyme (HRP) was cross-linked using glutaraldehyde in the presence of glass beads (solid-phase) bearing immobilized templates such as vancomycin and ampicillin. The cross-linking process links together proteins and protein chains, which in the presence of templates leads to the formation of permanent target-specific recognition sites without adverse effects on the enzymatic activity. Unlike complex protein engineering approaches commonly employed to generate affinity proteins, the method proposed can be used to produce protein-based ligands in a short time period using native protein molecules. These affinity materials are potentially useful tools especially for assays since they combine the catalytic properties of enzymes (for signaling) and molecular recognition properties of antibodies. We demonstrate this concept in an ELISA-format assay where HRP imprinted with vancomycin and ampicillin replaced traditional enzyme-antibody conjugates for selective detection of templates at micromolar concentrations. This approach can potentially provide a fast alternative to raising antibodies for targets that do not require high assay sensitivities; it can also find uses as a biochemical research tool, as a possible replacement for immunoperoxidase-conjugates.Here we introduce a new concept for synthesising molecularly imprinted nanoparticles by using proteins as macro-functional monomers. For a proof-of-concept, a model enzyme (HRP) was cross-linked using glutaraldehyde in the presence of glass beads (solid-phase) bearing immobilized templates such as vancomycin and ampicillin. The cross-linking process links together proteins and protein chains, which in the presence of templates leads to the formation of permanent target-specific recognition sites without adverse effects on the enzymatic activity. Unlike complex protein engineering approaches commonly employed to generate affinity proteins, the method proposed can be used to produce protein-based ligands in a short time period using native protein molecules. These affinity materials are potentially useful tools especially for assays since they combine the catalytic properties of enzymes (for signaling) and molecular recognition properties of antibodies. We demonstrate this concept in an ELISA-format assay where HRP imprinted with vancomycin and ampicillin replaced traditional enzyme-antibody conjugates for selective detection of templates at micromolar concentrations. This approach can potentially provide a fast alternative to raising antibodies for targets that do not require high assay sensitivities; it can also find uses as a biochemical research tool, as a possible replacement for immunoperoxidase-conjugates. Electronic supplementary information (ESI) available: Additional circular dichroism data and nanoparticle tracking analysis trace. See DOI: 10.1039/c6nr02009g
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Joseph, Christine G; Wilczynski, Andrzej; Holder, Jerry R; Xiang, Zhimin; Bauzo, Rayna M; Scott, Joseph W; Haskell-Luevano, Carrie
2003-12-01
Agouti-related protein (AGRP) is one of only two known endogenous antagonists of G-protein coupled receptors (GPCRs). Specifically, AGRP antagonizes the brain melanocortin-3 and -4 receptors involved in energy homeostasis, regulation of feeding behavior, and obesity. Alpha-melanocyte stimulating hormone (alpha-MSH) is one of the known endogenous agonists for these receptors. It has been hypothesized that the Arg-Phe-Phe (111-113) human AGRP amino acids may be mimicking the melanocortin agonist Phe-Arg-Trp (7-9) residue interactions with the melanocortin receptors that are important for both receptor molecular recognition and stimulation. To test this hypothesis, we generated thirteen chimeric peptide ligands based upon the melanocortin agonist peptides NDP-MSH (Ac-Ser-Tyr-Ser-Nle4-Glu-His-DPhe-Arg-Trp-Gly-Lys-Pro-Val-NH2) and MTII (Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH2). In these chimeric ligands, the agonist DPhe-Arg-Trp amino acids were replaced by the AGRP Arg-Phe-Phe residues, and resulted in agonist activity at the mouse melanocortin receptors (mMC1R and mMC3-5Rs), supporting the hypothesis that the AGRP antagonist ligand Arg-Phe-Phe residues mimic the agonist Phe-Arg-Trp amino acids. Interestingly, the Ac-Ser-Tyr-Ser-Nle4-Glu-His-Arg-DPhe-Phe-Gly-Lys-Pro-Val-NH2 peptide possessed 7 nM mMC1R agonist potency, and is 850-fold selective for the mMC1R versus the mMC3R, 2300-fold selective for the mMC1R versus the mMC4R, and 60-fold selective for the MC1R versus the mMC5R, resulting in the discovery of a new peptide template for the design of melanocortin receptor selective ligands.
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Collett, Gemma K; Brown, Clare M; Shaw, Tim J; White, Kahren M; Beale, Philip J; Anderiesz, Cleola; Barnes, David J
2017-01-01
Objectives Few interventions have been designed that provide standardised information to primary care clinicians about the diagnostic and treatment recommendations resulting from cancer multidisciplinary team (MDT) (tumour board) meetings. This study aimed to develop, implement and evaluate a standardised template for lung cancer MDTs to provide clinical information and treatment recommendations to general practitioners (GPs). Specific objectives were to (1) evaluate template feasibility (acceptability, appropriateness and timeliness) with GPs and (2) document processes of preimplementation, implementation and evaluation within the MDT setting. Design A mixed-method study design using structured interviews with GPs and qualitative documentation of project logs about implementation processes. Setting Two hospitals in Central Sydney, New South Wales, Australia. Participants: 61 GPs evaluated the template. Two lung cancer MDTs, consisting of 33 clinicians, and eight researchers participated in template development and implementation strategy. Results The MDT-reporting template appears to be a feasible way of providing clinical information to GPs following patient presentation at a lung cancer MDT meeting. Ninety-five per cent of GPs strongly agreed or agreed that the standardised template provided useful and relevant information, that it was received in a timely manner (90%) and that the information was easy to interpret and communicate to the patient (84%). Implementation process data show that the investment made in the preimplementation stage to integrate the template into standard work practices was a critical factor in successful implementation. Conclusions This study demonstrates that it is feasible to provide lung cancer MDT treatment recommendations to GPs through implementation of a standardised template. A simple intervention, such as a standardised template, can help to address quality gaps and ensure that timely information is communicated between tertiary and primary care healthcare providers. PMID:29288182
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Scheuner, Maren T; Hilborne, Lee; Brown, Julie; Lubin, Ira M
2012-07-01
Errors are most likely to occur during the pre- and postanalytic phases of the genetic testing process, which can contribute to underuse, overuse, and misuse of genetic tests. To mitigate these errors, we created a template for molecular genetic test reports that utilizes the combined features of synoptic reporting and narrative interpretation. A variation of the Delphi consensus process with an expert panel was used to create a draft report template, which was further informed by focus group discussions with primary care physicians. There was agreement that molecular genetic test reports should present information in groupings that flow in a logical manner, and most participants preferred the following order of presentation: patient and physician information, test performed, test results and interpretation, guidance on next steps, and supplemental information. We define data elements for the report as "required," "optional," "possible," and "not necessary"; provide recommendations regarding the grouping of these data elements; and describe the ideal design of the report template, including the preferred order of the report sections, formatting of data, and length of the report. With input from key stakeholders and building upon prior work, we created a template for molecular genetic test reports designed to improve clinical decision making at the point of care. The template design should lead to more effective communication between the laboratory and ordering clinician. Studies are needed to assess the usefulness and effectiveness of molecular genetic test reports generated using this template.
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Templated synthesis of metal nanorods in silica nanotubes
DOE Office of Scientific and Technical Information (OSTI.GOV)
Yin, Yadong; Gao, Chuanbo
A method of preparing a metal nanorod. The method includes seeding a metal nanoparticle within the lumen of a nanotube, and growing a metal nanorod from the seeded metal nanoparticle to form a metal nanorod-nanotube composite. In some cases, the nanotube includes metal binding ligands attached to the inner surface. Growing of the metal nanorod includes incubating the seeded nanotube in a solution that includes: a metal source for the metal in the metal nanorod, the metal source including an ion of the metal; a coordinating ligand that forms a stable complex with the metal ion; a reducing agent formore » reducing the metal ion, and a capping agent that stabilizes atomic monomers of the metal. Compositions derived from the method are also provided.« less
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Dai, Sheng; Burleigh, Mark C.; Shin, Yongsoon
2001-01-01
The present invention relates generally to mesoporous sorbent materials having high capacity, high selectivity, fast kinetics, and molecular recognition capability. The invention also relates to a process for preparing these mesoporous substrates through molecular imprinting techniques which differ from convention techniques in that a template molecule is bound to one end of bifunctional ligands to form a complex prior to binding of the bifunctional ligands to the substrate. The present invention also relates to methods of using the mesoporous sorbent materials, for example, in the separation of toxic metals from process effluents, paints, and other samples; detection of target molecules, such as amino acids, drugs, herbicides, fertilizers, and TNT, in samples; separation and/or detection of substances using chromatography; imaging agents; sensors; coatings; and composites.
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Hu, Xiaoshi; Lou, Xiaobing; Li, Chao; Yang, Qi; Chen, Qun; Hu, Bingwen
2018-05-02
Rational design and delicate control on the textural properties of metal-oxide materials for diverse structure-dependent applications still remain formidable challenges. Here, we present an eco-friendly and facile approach to smartly fabricate three-dimensional (3D) layer-by-layer manganese oxide (MnO x ) hierarchical mesoporous microcuboids from a Mn-MOF-74-based template, using a one-step solution-phase reaction scheme at room temperature. Through the controlled exchange of metal-organic framework (MOF) ligand with OH - in alkaline aqueous solution and in situ oxidation of manganese hydroxide intermediate, the Mn-MOF-74 template/precursor was readily converted to Mn 3 O 4 or δ-MnO 2 counterpart consisting of primary nanoparticle and nanosheet building blocks, respectively, with well-retained morphology. By X-ray diffraction, transmission electron microscopy (TEM), scanning electron microscopy, high-resolution TEM, N 2 adsorption-desorption analysis and other techniques, their crystal structure, detailed morphology, and microstructure features were unambiguously revealed. Specifically, their electrochemical Li-ion insertion/extraction properties were well evaluated, and it turns out that these unique 3D microcuboids could achieve a sustained superior lithium-storage performance especially at high rates benefited from the well-orchestrated structural characteristics (Mn 3 O 4 microcuboids: 890.7, 767.4, 560.1, and 437.1 mAh g -1 after 400 cycles at 0.2, 0.5, 1, and 2 A g -1 , respectively; δ-MnO 2 microcuboids: 991.5, 660.8, 504.4, and 362.1 mAh g -1 after 400 cycles at 0.2, 0.5, 1, and 2 A g -1 , respectively). To our knowledge, this is the most durable high-rate capability as well as the highest reversible capacity ever reported for pure MnO x anodes, which even surpass most of their hybrids. This facile, green, and economical strategy renews the traditional MOF-derived synthesis for highly tailorable functional materials and opens up new opportunities for metal-oxide electrodes with high performance.
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A semi-automatic computer-aided method for surgical template design
NASA Astrophysics Data System (ADS)
Chen, Xiaojun; Xu, Lu; Yang, Yue; Egger, Jan
2016-02-01
This paper presents a generalized integrated framework of semi-automatic surgical template design. Several algorithms were implemented including the mesh segmentation, offset surface generation, collision detection, ruled surface generation, etc., and a special software named TemDesigner was developed. With a simple user interface, a customized template can be semi- automatically designed according to the preoperative plan. Firstly, mesh segmentation with signed scalar of vertex is utilized to partition the inner surface from the input surface mesh based on the indicated point loop. Then, the offset surface of the inner surface is obtained through contouring the distance field of the inner surface, and segmented to generate the outer surface. Ruled surface is employed to connect inner and outer surfaces. Finally, drilling tubes are generated according to the preoperative plan through collision detection and merging. It has been applied to the template design for various kinds of surgeries, including oral implantology, cervical pedicle screw insertion, iliosacral screw insertion and osteotomy, demonstrating the efficiency, functionality and generality of our method.
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A semi-automatic computer-aided method for surgical template design
Chen, Xiaojun; Xu, Lu; Yang, Yue; Egger, Jan
2016-01-01
This paper presents a generalized integrated framework of semi-automatic surgical template design. Several algorithms were implemented including the mesh segmentation, offset surface generation, collision detection, ruled surface generation, etc., and a special software named TemDesigner was developed. With a simple user interface, a customized template can be semi- automatically designed according to the preoperative plan. Firstly, mesh segmentation with signed scalar of vertex is utilized to partition the inner surface from the input surface mesh based on the indicated point loop. Then, the offset surface of the inner surface is obtained through contouring the distance field of the inner surface, and segmented to generate the outer surface. Ruled surface is employed to connect inner and outer surfaces. Finally, drilling tubes are generated according to the preoperative plan through collision detection and merging. It has been applied to the template design for various kinds of surgeries, including oral implantology, cervical pedicle screw insertion, iliosacral screw insertion and osteotomy, demonstrating the efficiency, functionality and generality of our method. PMID:26843434
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A semi-automatic computer-aided method for surgical template design.
Chen, Xiaojun; Xu, Lu; Yang, Yue; Egger, Jan
2016-02-04
This paper presents a generalized integrated framework of semi-automatic surgical template design. Several algorithms were implemented including the mesh segmentation, offset surface generation, collision detection, ruled surface generation, etc., and a special software named TemDesigner was developed. With a simple user interface, a customized template can be semi- automatically designed according to the preoperative plan. Firstly, mesh segmentation with signed scalar of vertex is utilized to partition the inner surface from the input surface mesh based on the indicated point loop. Then, the offset surface of the inner surface is obtained through contouring the distance field of the inner surface, and segmented to generate the outer surface. Ruled surface is employed to connect inner and outer surfaces. Finally, drilling tubes are generated according to the preoperative plan through collision detection and merging. It has been applied to the template design for various kinds of surgeries, including oral implantology, cervical pedicle screw insertion, iliosacral screw insertion and osteotomy, demonstrating the efficiency, functionality and generality of our method.
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Christensen, Signe; Horowitz, Scott; Bardwell, James C.A.; Olsen, Johan G.; Willemoës, Martin; Lindorff-Larsen, Kresten; Ferkinghoff-Borg, Jesper; Hamelryck, Thomas; Winther, Jakob R.
2017-01-01
Despite the development of powerful computational tools, the full-sequence design of proteins still remains a challenging task. To investigate the limits and capabilities of computational tools, we conducted a study of the ability of the program Rosetta to predict sequences that recreate the authentic fold of thioredoxin. Focusing on the influence of conformational details in the template structures, we based our study on 8 experimentally determined template structures and generated 120 designs from each. For experimental evaluation, we chose six sequences from each of the eight templates by objective criteria. The 48 selected sequences were evaluated based on their progressive ability to (1) produce soluble protein in Escherichia coli and (2) yield stable monomeric protein, and (3) on the ability of the stable, soluble proteins to adopt the target fold. Of the 48 designs, we were able to synthesize 32, 20 of which resulted in soluble protein. Of these, only two were sufficiently stable to be purified. An X-ray crystal structure was solved for one of the designs, revealing a close resemblance to the target structure. We found a significant difference among the eight template structures to realize the above three criteria despite their high structural similarity. Thus, in order to improve the success rate of computational full-sequence design methods, we recommend that multiple template structures are used. Furthermore, this study shows that special care should be taken when optimizing the geometry of a structure prior to computational design when using a method that is based on rigid conformations. PMID:27659562
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Johansson, Kristoffer E; Tidemand Johansen, Nicolai; Christensen, Signe; Horowitz, Scott; Bardwell, James C A; Olsen, Johan G; Willemoës, Martin; Lindorff-Larsen, Kresten; Ferkinghoff-Borg, Jesper; Hamelryck, Thomas; Winther, Jakob R
2016-10-23
Despite the development of powerful computational tools, the full-sequence design of proteins still remains a challenging task. To investigate the limits and capabilities of computational tools, we conducted a study of the ability of the program Rosetta to predict sequences that recreate the authentic fold of thioredoxin. Focusing on the influence of conformational details in the template structures, we based our study on 8 experimentally determined template structures and generated 120 designs from each. For experimental evaluation, we chose six sequences from each of the eight templates by objective criteria. The 48 selected sequences were evaluated based on their progressive ability to (1) produce soluble protein in Escherichia coli and (2) yield stable monomeric protein, and (3) on the ability of the stable, soluble proteins to adopt the target fold. Of the 48 designs, we were able to synthesize 32, 20 of which resulted in soluble protein. Of these, only two were sufficiently stable to be purified. An X-ray crystal structure was solved for one of the designs, revealing a close resemblance to the target structure. We found a significant difference among the eight template structures to realize the above three criteria despite their high structural similarity. Thus, in order to improve the success rate of computational full-sequence design methods, we recommend that multiple template structures are used. Furthermore, this study shows that special care should be taken when optimizing the geometry of a structure prior to computational design when using a method that is based on rigid conformations. Copyright © 2016 Elsevier Ltd. All rights reserved.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Darawsheh, M. D.; Barrios, L. A.; Roubeau, O.
Ligand 1,3-bis(3-(pyridin-2-yl)-1H-pyrazol-5-yl)benzene, L, forms mononuclear spin crossover complexes [FeL 3] 2+ with pendant arms that cause them to dimerize through numerous intermolecular interactions forming supramolecular (X@[FeL 3] 2) 3+ cations. Finally, hey have the flexibility to encapsulate Cl -, Br - or I -, which allow tuning the magnetic properties, in the solid state and in solution.
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Darawsheh, M. D.; Barrios, L. A.; Roubeau, O.; ...
2016-12-05
Ligand 1,3-bis(3-(pyridin-2-yl)-1H-pyrazol-5-yl)benzene, L, forms mononuclear spin crossover complexes [FeL 3] 2+ with pendant arms that cause them to dimerize through numerous intermolecular interactions forming supramolecular (X@[FeL 3] 2) 3+ cations. Finally, hey have the flexibility to encapsulate Cl -, Br - or I -, which allow tuning the magnetic properties, in the solid state and in solution.
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Tognolini, Massimiliano; Incerti, Matteo; Mohamed, Iftiin Hassan; Giorgio, Carmine; Russo, Simonetta; Bruni, Renato; Lelli, Barbara; Bracci, Luisa; Noberini, Roberta; Pasquale, Elena B.; Barocelli, Elisabetta; Vicini, Paola; Mor, Marco
2012-01-01
The Eph–ephrin system, including the EphA2 receptor and the ephrin-A1 ligand, plays a critical role in tumor and vascular functions during carcinogenesis. We previously identified (3α,5β)-3-hydroxycholan-24-oic acid (lithocholic acid) as an Eph-ephrin antagonist able to inhibit EphA2 receptor activation and therefore potentially useful as a novel EphA2 receptor targeting agent. Here, we explore the structure-activity relationships of a focused set of lithocholic acid derivatives, based on molecular modelling investigation and displacement binding assays. Our exploration shows that while the 3-α-hydroxyl group of lithocholic acid has a negligible role in the recognition of the EphA2 receptor, its carboxylate group is critical for disrupting the binding of ephrin-A1 to the EphA2. As a result of our investigation, we identified (5β)-cholan-24-oic acid (cholanic acid) as a novel compound that competitively inhibits EphA2-ephrin-A1 interaction with higher potency than lithocholic acid. Surface plasmon resonance analysis indicates that cholanic acid binds specifically and reversibly to the ligand-binding domain of EphA2, with a steady-state dissociation constant (KD) in the low micromolar range. Furthermore, cholanic acid blocks the phosphorylation of EphA2 and cell retraction and rounding in PC3 prostate cancer cells, two effects that depend on EphA2 activation by the ephrin-A1 ligand. These findings suggest that cholanic acid can be used as a template structure to design effective EphA2 antagonists, with potential impact in the elucidation of the role played by this receptor in pathological conditions. PMID:22529030
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The heterodimeric sweet taste receptor has multiple potential ligand binding sites.
Cui, Meng; Jiang, Peihua; Maillet, Emeline; Max, Marianna; Margolskee, Robert F; Osman, Roman
2006-01-01
The sweet taste receptor is a heterodimer of two G protein coupled receptors, T1R2 and T1R3. This discovery has increased our understanding at the molecular level of the mechanisms underlying sweet taste. Previous experimental studies using sweet receptor chimeras and mutants show that there are at least three potential binding sites in this heterodimeric receptor. Receptor activity toward the artificial sweeteners aspartame and neotame depends on residues in the amino terminal domain of human T1R2. In contrast, receptor activity toward the sweetener cyclamate and the sweet taste inhibitor lactisole depends on residues within the transmembrane domain of human T1R3. Furthermore, receptor activity toward the sweet protein brazzein depends on the cysteine rich domain of human T1R3. Although crystal structures are not available for the sweet taste receptor, useful homology models can be developed based on appropriate templates. The amino terminal domain, cysteine rich domain and transmembrane helix domain of T1R2 and T1R3 have been modeled based on the crystal structures of metabotropic glutamate receptor type 1, tumor necrosis factor receptor, and bovine rhodopsin, respectively. We have used homology models of the sweet taste receptors, molecular docking of sweet ligands to the receptors, and site-directed mutagenesis of the receptors to identify potential ligand binding sites of the sweet taste receptor. These studies have led to a better understanding of the structure and function of this heterodimeric receptor, and can act as a guide for rational structure-based design of novel non-caloric sweeteners, which can be used in the fighting against obesity and diabetes.
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Davey, James A; Chica, Roberto A
2015-04-01
Computational protein design (CPD) predictions are highly dependent on the structure of the input template used. However, it is unclear how small differences in template geometry translate to large differences in stability prediction accuracy. Herein, we explored how structural changes to the input template affect the outcome of stability predictions by CPD. To do this, we prepared alternate templates by Rotamer Optimization followed by energy Minimization (ROM) and used them to recapitulate the stability of 84 protein G domain β1 mutant sequences. In the ROM process, side-chain rotamers for wild-type (WT) or mutant sequences are optimized on crystal or nuclear magnetic resonance (NMR) structures prior to template minimization, resulting in alternate structures termed ROM templates. We show that use of ROM templates prepared from sequences known to be stable results predominantly in improved prediction accuracy compared to using the minimized crystal or NMR structures. Conversely, ROM templates prepared from sequences that are less stable than the WT reduce prediction accuracy by increasing the number of false positives. These observed changes in prediction outcomes are attributed to differences in side-chain contacts made by rotamers in ROM templates. Finally, we show that ROM templates prepared from sequences that are unfolded or that adopt a nonnative fold result in the selective enrichment of sequences that are also unfolded or that adopt a nonnative fold, respectively. Our results demonstrate the existence of a rotamer bias caused by the input template that can be harnessed to skew predictions toward sequences displaying desired characteristics. © 2014 The Protein Society.
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Usefulness of an Osteotomy Template for Skull Tumorectomy and Simultaneous Skull Reconstruction.
Oji, Tomito; Sakamoto, Yoshiaki; Miwa, Tomoru; Nakagawa, Yu; Yoshida, Kazunari; Kishi, Kazuo
2016-09-01
Simultaneous tumor resection and cranioplasty with hydroxyapatite osteosynthesis are sometimes necessary in patients of skull neoplasms or skull-invasive tumors. However, the disadvantage of simultaneous surgery is that mismatches often occur between the skull defect and the hydroxyapatite implant. To solve this problem, the authors developed a customized template for designing the craniotomy line. Before each operation, the craniotomy design was discussed with a neurosurgeon. Based on the discussion, 2 hydroxyapatite implants were customized for each patient on the basis of models prepared using computed tomography data. The first implant was an onlay template for the preoperative cranium, which was customized for designing the osteotomy line. The other implant was used for the skull defect. Using the template, the osteotomy line was drawn along the template edge, osteotomy was performed along this line, and the implant was placed in the skull defect. This technique was performed in 3 patients. No implant or defect trimming was required in any patient, good cosmetic outcomes were noted in all patients, and no complications occurred. Use of predesigned hydroxyapatite templates for craniotomy during simultaneous skull tumor resection and cranioplasty has some clinical advantages: the precise craniotomy line can be designed, the implant and skull defect fit better and show effective osteoconduction, trimming of the implant or defect is minimized, and the operation time is shortened.
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Mongkolwat, Pattanasak; Channin, David S; Kleper, Vladimir; Rubin, Daniel L
2012-01-01
In a routine clinical environment or clinical trial, a case report form or structured reporting template can be used to quickly generate uniform and consistent reports. Annotation and image markup (AIM), a project supported by the National Cancer Institute's cancer biomedical informatics grid, can be used to collect information for a case report form or structured reporting template. AIM is designed to store, in a single information source, (a) the description of pixel data with use of markups or graphical drawings placed on the image, (b) calculation results (which may or may not be directly related to the markups), and (c) supplemental information. To facilitate the creation of AIM annotations with data entry templates, an AIM template schema and an open-source template creation application were developed to assist clinicians, image researchers, and designers of clinical trials to quickly create a set of data collection items, thereby ultimately making image information more readily accessible.
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Channin, David S.; Rubin, Vladimir Kleper Daniel L.
2012-01-01
In a routine clinical environment or clinical trial, a case report form or structured reporting template can be used to quickly generate uniform and consistent reports. Annotation and Image Markup (AIM), a project supported by the National Cancer Institute’s cancer Biomedical Informatics Grid, can be used to collect information for a case report form or structured reporting template. AIM is designed to store, in a single information source, (a) the description of pixel data with use of markups or graphical drawings placed on the image, (b) calculation results (which may or may not be directly related to the markups), and (c) supplemental information. To facilitate the creation of AIM annotations with data entry templates, an AIM template schema and an open-source template creation application were developed to assist clinicians, image researchers, and designers of clinical trials to quickly create a set of data collection items, thereby ultimately making image information more readily accessible. © RSNA, 2012 PMID:22556315
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Design and installation of a subsea multiwell drilling template at Garden Banks Block 189
DOE Office of Scientific and Technical Information (OSTI.GOV)
Domangue, R.J.
1991-09-01
This paper describes the economics, design, and installation of a simple drilling template that was used to retain or save subsea exploratory and delineation wells in Garden Banks Block 189 (GB 189) in the Gulf of Mexico.
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Homology Modeling of Class A G Protein-Coupled Receptors
Costanzi, Stefano
2012-01-01
G protein-coupled receptors (GPCRs) are a large superfamily of membrane bound signaling proteins that hold great pharmaceutical interest. Since experimentally elucidated structures are available only for a very limited number of receptors, homology modeling has become a widespread technique for the construction of GPCR models intended to study the structure-function relationships of the receptors and aid the discovery and development of ligands capable of modulating their activity. Through this chapter, various aspects involved in the constructions of homology models of the serpentine domain of the largest class of GPCRs, known as class A or rhodopsin family, are illustrated. In particular, the chapter provides suggestions, guidelines and critical thoughts on some of the most crucial aspect of GPCR modeling, including: collection of candidate templates and a structure-based alignment of their sequences; identification and alignment of the transmembrane helices of the query receptor to the corresponding domains of the candidate templates; selection of one or more templates receptor; election of homology or de novo modeling for the construction of specific extracellular and intracellular domains; construction of the three-dimensional models, with special consideration to extracellular regions, disulfide bridges, and interhelical cavity; validation of the models through controlled virtual screening experiments. PMID:22323225
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ERIC Educational Resources Information Center
Dalziel, James; Dalziel, Bronwen
2012-01-01
One of the ongoing challenges in the field of Learning Design is how to most effectively support educators in the development of innovative e-learning through the adoption and adaptation of learning design templates. This paper reflects on experiences from two recent higher education projects in teacher training and medical education, and…
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Structure-Based Predictions of Activity Cliffs
Husby, Jarmila; Bottegoni, Giovanni; Kufareva, Irina; Abagyan, Ruben; Cavalli, Andrea
2015-01-01
In drug discovery, it is generally accepted that neighboring molecules in a given descriptors' space display similar activities. However, even in regions that provide strong predictability, structurally similar molecules can occasionally display large differences in potency. In QSAR jargon, these discontinuities in the activity landscape are known as ‘activity cliffs’. In this study, we assessed the reliability of ligand docking and virtual ligand screening schemes in predicting activity cliffs. We performed our calculations on a diverse, independently collected database of cliff-forming co-crystals. Starting from ideal situations, which allowed us to establish our baseline, we progressively moved toward simulating more realistic scenarios. Ensemble- and template-docking achieved a significant level of accuracy, suggesting that, despite the well-known limitations of empirical scoring schemes, activity cliffs can be accurately predicted by advanced structure-based methods. PMID:25918827
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Computational Methods in Drug Discovery
Sliwoski, Gregory; Kothiwale, Sandeepkumar; Meiler, Jens
2014-01-01
Computer-aided drug discovery/design methods have played a major role in the development of therapeutically important small molecules for over three decades. These methods are broadly classified as either structure-based or ligand-based methods. Structure-based methods are in principle analogous to high-throughput screening in that both target and ligand structure information is imperative. Structure-based approaches include ligand docking, pharmacophore, and ligand design methods. The article discusses theory behind the most important methods and recent successful applications. Ligand-based methods use only ligand information for predicting activity depending on its similarity/dissimilarity to previously known active ligands. We review widely used ligand-based methods such as ligand-based pharmacophores, molecular descriptors, and quantitative structure-activity relationships. In addition, important tools such as target/ligand data bases, homology modeling, ligand fingerprint methods, etc., necessary for successful implementation of various computer-aided drug discovery/design methods in a drug discovery campaign are discussed. Finally, computational methods for toxicity prediction and optimization for favorable physiologic properties are discussed with successful examples from literature. PMID:24381236
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NASA Astrophysics Data System (ADS)
Comitani, Federico; Cohen, Netta; Ashby, Jamie; Botten, Dominic; Lummis, Sarah C. R.; Molteni, Carla
2014-01-01
The resistance to dieldrin (RDL) receptor is an insect pentameric ligand-gated ion channel (pLGIC). It is activated by the neurotransmitter γ-aminobutyric acid (GABA) binding to its extracellular domain; hence elucidating the atomistic details of this interaction is important for understanding how the RDL receptor functions. As no high resolution structures are currently available, we built homology models of the extracellular domain of the RDL receptor using different templates, including the widely used acetylcholine binding protein and two pLGICs, the Erwinia Chrysanthemi ligand-gated ion channel (ELIC) and the more recently resolved GluCl. We then docked GABA into the selected three dimensional structures, which we used as starting points for classical molecular dynamics simulations. This allowed us to analyze in detail the behavior of GABA in the binding sites, including the hydrogen bond and cation-π interaction networks it formed, the conformers it visited and the possible role of water molecules in mediating the interactions; we also estimated the binding free energies. The models were all stable and showed common features, including interactions consistent with experimental data and similar to other pLGICs; differences could be attributed to the quality of the models, which increases with increasing sequence identity, and the use of a pLGIC template. We supplemented the molecular dynamics information with metadynamics, a rare event method, by exploring the free energy landscape of GABA binding to the RDL receptor. Overall, we show that the GluCl template provided the best models. GABA forming direct salt-bridges with Arg211 and Glu204, and cation-π interactions with an aromatic cage including Tyr109, Phe206 and Tyr254, represents a favorable binding arrangement, and the interaction with Glu204 can also be mediated by a water molecule.
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Optical Control of Dopamine Receptors Using a Photoswitchable Tethered Inverse Agonist.
Donthamsetti, Prashant C; Winter, Nils; Schönberger, Matthias; Levitz, Joshua; Stanley, Cherise; Javitch, Jonathan A; Isacoff, Ehud Y; Trauner, Dirk
2017-12-27
Family A G protein-coupled receptors (GPCRs) control diverse biological processes and are of great clinical relevance. Their archetype rhodopsin becomes naturally light sensitive by binding covalently to the photoswitchable tethered ligand (PTL) retinal. Other GPCRs, however, neither bind covalently to ligands nor are light sensitive. We sought to impart the logic of rhodopsin to light-insensitive Family A GPCRs in order to enable their remote control in a receptor-specific, cell-type-specific, and spatiotemporally precise manner. Dopamine receptors (DARs) are of particular interest for their roles in motor coordination, appetitive, and aversive behavior, as well as neuropsychiatric disorders such as Parkinson's disease, schizophrenia, mood disorders, and addiction. Using an azobenzene derivative of the well-known DAR ligand 2-(N-phenethyl-N-propyl)amino-5-hydroxytetralin (PPHT), we were able to rapidly, reversibly, and selectively block dopamine D1 and D2 receptors (D1R and D2R) when the PTL was conjugated to an engineered cysteine near the dopamine binding site. Depending on the site of tethering, the ligand behaved as either a photoswitchable tethered neutral antagonist or inverse agonist. Our results indicate that DARs can be chemically engineered for selective remote control by light and provide a template for precision control of Family A GPCRs.
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Hollow-structured mesoporous materials: chemical synthesis, functionalization and applications.
Li, Yongsheng; Shi, Jianlin
2014-05-28
Hollow-structured mesoporous materials (HMMs), as a kind of mesoporous material with unique morphology, have been of great interest in the past decade because of the subtle combination of the hollow architecture with the mesoporous nanostructure. Benefitting from the merits of low density, large void space, large specific surface area, and, especially, the good biocompatibility, HMMs present promising application prospects in various fields, such as adsorption and storage, confined catalysis when catalytically active species are incorporated in the core and/or shell, controlled drug release, targeted drug delivery, and simultaneous diagnosis and therapy of cancers when the surface and/or core of the HMMs are functionalized with functional ligands and/or nanoparticles, and so on. In this review, recent progress in the design, synthesis, functionalization, and applications of hollow mesoporous materials are discussed. Two main synthetic strategies, soft-templating and hard-templating routes, are broadly sorted and described in detail. Progress in the main application aspects of HMMs, such as adsorption and storage, catalysis, and biomedicine, are also discussed in detail in this article, in terms of the unique features of the combined large void space in the core and the mesoporous network in the shell. Functionalization of the core and pore/outer surfaces with functional organic groups and/or nanoparticles, and their performance, are summarized in this article. Finally, an outlook of their prospects and challenges in terms of their controlled synthesis and scaled application is presented. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Experiment Management System for the SND Detector
NASA Astrophysics Data System (ADS)
Pugachev, K.
2017-10-01
We present a new experiment management system for the SND detector at the VEPP-2000 collider (Novosibirsk). An important part to report about is access to experimental databases (configuration, conditions and metadata). The system is designed in client-server architecture. User interaction comes true using web-interface. The server side includes several logical layers: user interface templates; template variables description and initialization; implementation details. The templates are meant to involve as less IT knowledge as possible. Experiment configuration, conditions and metadata are stored in a database. To implement the server side Node.js, a modern JavaScript framework, has been chosen. A new template engine having an interesting feature is designed. A part of the system is put into production. It includes templates dealing with showing and editing first level trigger configuration and equipment configuration and also showing experiment metadata and experiment conditions data index.
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Mode-dependent templates and scan order for H.264/AVC-based intra lossless coding.
Gu, Zhouye; Lin, Weisi; Lee, Bu-Sung; Lau, Chiew Tong; Sun, Ming-Ting
2012-09-01
In H.264/advanced video coding (AVC), lossless coding and lossy coding share the same entropy coding module. However, the entropy coders in the H.264/AVC standard were original designed for lossy video coding and do not yield adequate performance for lossless video coding. In this paper, we analyze the problem with the current lossless coding scheme and propose a mode-dependent template (MD-template) based method for intra lossless coding. By exploring the statistical redundancy of the prediction residual in the H.264/AVC intra prediction modes, more zero coefficients are generated. By designing a new scan order for each MD-template, the scanned coefficients sequence fits the H.264/AVC entropy coders better. A fast implementation algorithm is also designed. With little computation increase, experimental results confirm that the proposed fast algorithm achieves about 7.2% bit saving compared with the current H.264/AVC fidelity range extensions high profile.
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NASA Astrophysics Data System (ADS)
Welter, Petra; Deserno, Thomas M.; Gülpers, Ralph; Wein, Berthold B.; Grouls, Christoph; Günther, Rolf W.
2010-03-01
The large and continuously growing amount of medical image data demands access methods with regards to content rather than simple text-based queries. The potential benefits of content-based image retrieval (CBIR) systems for computer-aided diagnosis (CAD) are evident and have been approved. Still, CBIR is not a well-established part of daily routine of radiologists. We have already presented a concept of CBIR integration for the radiology workflow in accordance with the Integrating the Healthcare Enterprise (IHE) framework. The retrieval result is composed as a Digital Imaging and Communication in Medicine (DICOM) Structured Reporting (SR) document. The use of DICOM SR provides interchange with PACS archive and image viewer. It offers the possibility of further data mining and automatic interpretation of CBIR results. However, existing standard templates do not address the domain of CBIR. We present a design of a SR template customized for CBIR. Our approach is based on the DICOM standard templates and makes use of the mammography and chest CAD SR templates. Reuse of approved SR sub-trees promises a reliable design which is further adopted to the CBIR domain. We analyze the special CBIR requirements and integrate the new concept of similar images into our template. Our approach also includes the new concept of a set of selected images for defining the processed images for CBIR. A commonly accepted pre-defined template for the presentation and exchange of results in a standardized format promotes the widespread application of CBIR in radiological routine.
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Design of protein-responsive micro-sized hydrogels for self-regulating microfluidic systems
NASA Astrophysics Data System (ADS)
Hirayama, Mayu; Tsuruta, Kazuhiro; Kawamura, Akifumi; Ohara, Masayuki; Shoji, Kan; Kawano, Ryuji; Miyata, Takashi
2018-03-01
Diagnosis sensors using micro-total analysis systems (µ-TAS) have been developed for detecting target biomolecules such as proteins and saccharides because they are signal biomolecules for monitoring body conditions and diseases. In this study, biomolecularly stimuli-responsive micro-sized hydrogels that exhibited quick shrinkage in response to lectin concanavalinA (ConA) were prepared in a microchannel by photopolymerization using a fluorescence microscope. In preparing the micro-size hydrogels, glycosyloxyethyl methacrylate (GEMA) as a ligand monomer was copolymerized with a crosslinker in the presence of template ConA in molecular imprinting. The ConA-imprinted micro-hydrogel showed greater shrinkage in response to target ConA than nonimprinted micro-hydrogel. When a buffer solution was switched to an aqueous ConA solution in the Y-shaped microchannel, the flow rates changed quickly because of the responsive shrinkage of the micro-hydrogel prepared in the microchannel. These results suggest that the ConA-imprinted micro-hydrogel acted as a self-regulated microvalve in microfluidic systems.
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C-Glycosyl Analogs of Oligosaccharides
NASA Astrophysics Data System (ADS)
Vauzeilles, Boris; Urban, Dominique; Doisneau, Gilles; Beau, Jean-Marie
This chapter covers the synthesis of a large collection of "C-oligosaccharides ", synthetic analogs of naturally occurring oligosaccharides in which a carbon atom replaces the anomeric, interglycosidic oxygen atom. These non-natural constructs are stable to chemical and enzymatic degradation, and are primarily devised to probe carbohydrate-based biological processes. These mainly target carbohydrate-protein interactions such as the modulation of glycoenzyme (glycosylhydrolases and transferases) activities or the design of ligands for lectin Carbohydrate Recognition Domains. The discussion is based on the key carbon-carbon bond assembling steps on carbohydrate templates: ionic (anionic and cationic chemistries, sigmatropic rearrangements) or radical assemblage, and olefin metathesis. Synthetic schemes in which at least one of the monosaccharide units is constructed by total synthesis or by cyclization of acyclic chiral chains are presented separately in a "partial de novo synthesis" section. The review also provides comments, when they are known, on the conformational and binding properties of these synthetic analogs, as well as their biological behavior when tested.
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Toxins and derivatives in molecular pharmaceutics: Drug delivery and targeted therapy.
Zhan, Changyou; Li, Chong; Wei, Xiaoli; Lu, Wuyuan; Lu, Weiyue
2015-08-01
Protein and peptide toxins offer an invaluable source for the development of actively targeted drug delivery systems. They avidly bind to a variety of cognate receptors, some of which are expressed or even up-regulated in diseased tissues and biological barriers. Protein and peptide toxins or their derivatives can act as ligands to facilitate tissue- or organ-specific accumulation of therapeutics. Some toxins have evolved from a relatively small number of structural frameworks that are particularly suitable for addressing the crucial issues of potency and stability, making them an instrumental source of leads and templates for targeted therapy. The focus of this review is on protein and peptide toxins for the development of targeted drug delivery systems and molecular therapies. We summarize disease- and biological barrier-related toxin receptors, as well as targeted drug delivery strategies inspired by those receptors. The design of new therapeutics based on protein and peptide toxins is also discussed. Copyright © 2015 Elsevier B.V. All rights reserved.
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Joseph, C G; Sorensen, N B; Wood, M S; Xiang, Z; Moore, M C; Haskell-Luevano, C
2005-11-01
The Ac-His-dPhe-Arg-Trp-NH2 tetrapeptide is a nonselective melanocortin agonist and replacement of Arg in the tetrapeptide with acidic, basic or neutral amino acids results in reduced potency at the melanocortin receptor (MCR) isoforms (MC1R and MC3-5R). To determine the importance of the positive charge and the guanidine moiety for melanocortin activity, a series of urea- and thiourea-substituted tetrapeptides were designed. Replacement of Arg with Lys or ornithine reduced agonist activity at the mouse mMC1 and mMC3-5 receptors, thus supporting the hypothesis that the guanidine moiety is important for receptor potency, particularly at the MC3-5 receptors. The Arg side chain-modified tetrapeptides examined in this study include substituted phenyl, naphthyl, and aliphatic urea and thiourea residues using a Lys side-chain template. These ligands elicit full-agonist pharmacology at the mouse MCRs examined in this study.
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2011-01-01
Supporting functional molecules on crystal facets is an established technique in nanotechnology. To preserve the original activity of ionic metallorganic agents on a supporting template, conservation of the charge and oxidation state of the active center is indispensable. We present a model system of a metallorganic agent that, indeed, fulfills this design criterion on a technologically relevant metal support with potential impact on Au(III)-porphyrin-functionalized nanoparticles for an improved anticancer-drug delivery. Employing scanning tunneling microscopy and -spectroscopy in combination with photoemission spectroscopy, we clarify at the single-molecule level the underlying mechanisms of this exceptional adsorption mode. It is based on the balance between a high-energy oxidation state and an electrostatic screening-response of the surface (image charge). Modeling with first principles methods reveals submolecular details of the metal–ligand bonding interaction and completes the study by providing an illustrative electrostatic model relevant for ionic metalorganic agent molecules, in general. PMID:21736315
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Singh, Durg Vijay; Agarwal, Shikha; Kesharwani, Rajesh Kumar; Misra, Krishna
2012-08-01
Isoproturon is the only herbicide that can control Phalaris minor, a competitive weed of wheat that developed resistance in 1992. Resistance against isoproturon was reported to be due to a mutation in the psbA gene that encodes the isoproturon-binding D1 protein. Previously in our laboratory, a triazole derivative of isoproturon (TDI) was synthesized and found to be active against both susceptible and resistant biotypes at 0.5 kg/ha but has shown poor specificity. In the present study, both susceptible D1((S)), resistant D1((R)) and D2 proteins of the PS-II reaction center of P. minor have been modeled and simulated, selecting the crystal structure of PS-II from Thermosynechococcus elongatus (2AXT.pdb) as template. Loop regions were refined, and the complete reaction center D1/D2 was simulated with GROMACS in lipid (1-palmitoyl-2-oleoylglycero-3-phosphoglycerol, POPG) environment along with ligands and cofactor. Both S and R models were energy minimized using steepest decent equilibrated with isotropic pressure coupling and temperature coupling using a Berendsen protocol, and subjected to 1,000 ps of MD simulation. As a result of MD simulation, the best model obtained in lipid environment had five chlorophylls, two plastoquinones, two phenophytins and a bicarbonate ion along with cofactor Fe and oxygen evolving center (OEC). The triazole derivative of isoproturon was used as lead molecule for docking. The best worked out conformation of TDI was chosen for receptor-based de novo ligand design. In silico designed molecules were screened and, as a result, only those molecules that show higher docking and binding energies in comparison to isoproturon and its triazole derivative were proposed for synthesis in order to get more potent, non-resistant and more selective TDI analogs.
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Cramer, Richard D.
2015-01-01
The possible applicability of the new template CoMFA methodology to the prediction of unknown biological affinities was explored. For twelve selected targets, all ChEMBL binding affinities were used as training and/or prediction sets, making these 3D-QSAR models the most structurally diverse and among the largest ever. For six of the targets, X-ray crystallographic structures provided the aligned templates required as input (BACE, cdk1, chk2, carbonic anhydrase-II, factor Xa, PTP1B). For all targets including the other six (hERG, cyp3A4 binding, endocrine receptor, COX2, D2, and GABAa), six modeling protocols applied to only three familiar ligands provided six alternate sets of aligned templates. The statistical qualities of the six or seven models thus resulting for each individual target were remarkably similar. Also, perhaps unexpectedly, the standard deviations of the errors of cross-validation predictions accompanying model derivations were indistinguishable from the standard deviations of the errors of truly prospective predictions. These standard deviations of prediction ranged from 0.70 to 1.14 log units and averaged 0.89 (8x in concentration units) over the twelve targets, representing an average reduction of almost 50% in uncertainty, compared to the null hypothesis of “predicting” an unknown affinity to be the average of known affinities. These errors of prediction are similar to those from Tanimoto coefficients of fragment occurrence frequencies, the predominant approach to side effect prediction, which template CoMFA can augment by identifying additional active structural classes, by improving Tanimoto-only predictions, by yielding quantitative predictions of potency, and by providing interpretable guidance for avoiding or enhancing any specific target response. PMID:26065424
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Risk based decision tool for space exploration missions
NASA Technical Reports Server (NTRS)
Meshkat, Leila; Cornford, Steve; Moran, Terrence
2003-01-01
This paper presents an approach and corresponding tool to assess and analyze the risks involved in a mission during the pre-phase A design process. This approach is based on creating a risk template for each subsystem expert involved in the mission design process and defining appropriate interactions between the templates.
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Autonomy among Thieves: Template Course Design for Student and Faculty Success
ERIC Educational Resources Information Center
Huun, Kathleen; Hughes, Lisa
2014-01-01
Responding to a student-expressed need for consistency among courses within the online Baccalaureate Nursing Completion program at Midwestern University, an instructional designer and nursing faculty member collaborated to build a course evaluation rubric, learning management system template, and corresponding matrix to help support student…
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M13-templated magnetic nanoparticles for targeted in vivo imaging of prostate cancer
NASA Astrophysics Data System (ADS)
Ghosh, Debadyuti; Lee, Youjin; Thomas, Stephanie; Kohli, Aditya G.; Yun, Dong Soo; Belcher, Angela M.; Kelly, Kimberly A.
2012-10-01
Molecular imaging allows clinicians to visualize the progression of tumours and obtain relevant information for patient diagnosis and treatment. Owing to their intrinsic optical, electrical and magnetic properties, nanoparticles are promising contrast agents for imaging dynamic molecular and cellular processes such as protein-protein interactions, enzyme activity or gene expression. Until now, nanoparticles have been engineered with targeting ligands such as antibodies and peptides to improve tumour specificity and uptake. However, excessive loading of ligands can reduce the targeting capabilities of the ligand and reduce the ability of the nanoparticle to bind to a finite number of receptors on cells. Increasing the number of nanoparticles delivered to cells by each targeting molecule would lead to higher signal-to-noise ratios and would improve image contrast. Here, we show that M13 filamentous bacteriophage can be used as a scaffold to display targeting ligands and multiple nanoparticles for magnetic resonance imaging of cancer cells and tumours in mice. Monodisperse iron oxide magnetic nanoparticles assemble along the M13 coat, and its distal end is engineered to display a peptide that targets SPARC glycoprotein, which is overexpressed in various cancers. Compared with nanoparticles that are directly functionalized with targeting peptides, our approach improves contrast because each SPARC-targeting molecule delivers a large number of nanoparticles into the cells. Moreover, the targeting ligand and nanoparticles could be easily exchanged for others, making this platform attractive for in vivo high-throughput screening and molecular detection.
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M13-templated magnetic nanoparticles for targeted in vivo imaging of prostate cancer.
Ghosh, Debadyuti; Lee, Youjin; Thomas, Stephanie; Kohli, Aditya G; Yun, Dong Soo; Belcher, Angela M; Kelly, Kimberly A
2012-10-01
Molecular imaging allows clinicians to visualize the progression of tumours and obtain relevant information for patient diagnosis and treatment. Owing to their intrinsic optical, electrical and magnetic properties, nanoparticles are promising contrast agents for imaging dynamic molecular and cellular processes such as protein-protein interactions, enzyme activity or gene expression. Until now, nanoparticles have been engineered with targeting ligands such as antibodies and peptides to improve tumour specificity and uptake. However, excessive loading of ligands can reduce the targeting capabilities of the ligand and reduce the ability of the nanoparticle to bind to a finite number of receptors on cells. Increasing the number of nanoparticles delivered to cells by each targeting molecule would lead to higher signal-to-noise ratios and would improve image contrast. Here, we show that M13 filamentous bacteriophage can be used as a scaffold to display targeting ligands and multiple nanoparticles for magnetic resonance imaging of cancer cells and tumours in mice. Monodisperse iron oxide magnetic nanoparticles assemble along the M13 coat, and its distal end is engineered to display a peptide that targets SPARC glycoprotein, which is overexpressed in various cancers. Compared with nanoparticles that are directly functionalized with targeting peptides, our approach improves contrast because each SPARC-targeting molecule delivers a large number of nanoparticles into the cells. Moreover, the targeting ligand and nanoparticles could be easily exchanged for others, making this platform attractive for in vivo high-throughput screening and molecular detection.
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M13-templated magnetic nanoparticles for targeted in vivo imaging of prostate cancer
Ghosh, Debadyuti; Lee, Youjin; Thomas, Stephanie; Kohli, Aditya G.; Yun, Dong Soo; Belcher, Angela M.; Kelly, Kimberly A.
2014-01-01
Molecular imaging allows clinicians to visualize the progression of tumours and obtain relevant information for patient diagnosis and treatment1. Owing to their intrinsic optical, electrical and magnetic properties, nanoparticles are promising contrast agents for imaging dynamic molecular and cellular processes such as protein-protein interactions, enzyme activity or gene expression2. Until now, nanoparticles have been engineered with targeting ligands such as antibodies and peptides to improve tumour specificity and uptake. However, excessive loading of ligands can reduce the targeting capabilities of the ligand3,4,5 and reduce the ability of the nanoparticle to bind to a finite number of receptors on cells6. Increasing the number of nanoparticles delivered to cells by each targeting molecule would lead to higher signal-to-noise ratios and improve image contrast. Here, we show that M13 filamentous bacteriophage can be used as a scaffold to display targeting ligands and multiple nanoparticles for magnetic resonance imaging of cancer cells and tumours in mice. Monodisperse iron oxide magnetic nanoparticles assemble along the M13 coat, and its distal end is engineered to display a peptide that targets SPARC glycoprotein, which is overexpressed in various cancers. Compared with nanoparticles that are directly functionalized with targeting peptides, our approach improves contrast because each SPARC-targeting molecule delivers a large number of nanoparticles into the cells. Moreover, the targeting ligand and nanoparticles could be easily exchanged for others, making this platform attractive for in vivo high-throughput screening and molecular detection. PMID:22983492
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Yi, He; Bao, Xin-Yu; Tiberio, Richard; Wong, H-S Philip
2015-02-11
Directed self-assembly (DSA) is a promising lithography candidate for technology nodes beyond 14 nm. Researchers have shown contact hole patterning for random logic circuits using DSA with small physical templates. This paper introduces an alphabet approach that uses a minimal set of small physical templates to pattern all contacts configurations on integrated circuits. We illustrate, through experiments, a general and scalable template design strategy that links the DSA material properties to the technology node requirements.
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Logistic Map for Cancellable Biometrics
NASA Astrophysics Data System (ADS)
Supriya, V. G., Dr; Manjunatha, Ramachandra, Dr
2017-08-01
This paper presents design and implementation of secured biometric template protection system by transforming the biometric template using binary chaotic signals and 3 different key streams to obtain another form of template and demonstrating its efficiency by the results and investigating on its security through analysis including, key space analysis, information entropy and key sensitivity analysis.
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A Template-Based Protein Structure Reconstruction Method Using Deep Autoencoder Learning.
Li, Haiou; Lyu, Qiang; Cheng, Jianlin
2016-12-01
Protein structure prediction is an important problem in computational biology, and is widely applied to various biomedical problems such as protein function study, protein design, and drug design. In this work, we developed a novel deep learning approach based on a deeply stacked denoising autoencoder for protein structure reconstruction. We applied our approach to a template-based protein structure prediction using only the 3D structural coordinates of homologous template proteins as input. The templates were identified for a target protein by a PSI-BLAST search. 3DRobot (a program that automatically generates diverse and well-packed protein structure decoys) was used to generate initial decoy models for the target from the templates. A stacked denoising autoencoder was trained on the decoys to obtain a deep learning model for the target protein. The trained deep model was then used to reconstruct the final structural model for the target sequence. With target proteins that have highly similar template proteins as benchmarks, the GDT-TS score of the predicted structures is greater than 0.7, suggesting that the deep autoencoder is a promising method for protein structure reconstruction.
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Su, Yanping; Chen, Chun; Zhu, Xiaoguang; Zhang, Yong; Gong, Wanbing; Zhang, Haimin; Zhao, Huijun; Wang, Guozhong
2017-05-16
We report a fast and simple method for the synthesis of Ni-based metal-organic-frameworks (Ni-MOFs). Due to the existence of nickel ions and an organic ligand, the MOFs are employed as a sacrificial template for the facile preparation of carbon-embedded Ni (Ni/C) catalysts by a direct thermal decomposition method. The obtained Ni/C catalysts exhibit excellent catalytic activity for selectively transforming furfural (FAL) to tetrahydrofurfuryl alcohol (THFOL) due to the Ni nanoparticles (NPs) embedded uniformly in the ligand-derived carbon. The exemplified results illustrate that the catalytic performance of the Ni/C catalyst is greatly affected by the calcination conditions (temperature and time), composition of the Ni-MOF precursor and the catalysis conditions. The conversion of FAL and selectivity of THFOL both reached 100% under the conditions of 120 °C, 1 MPa H 2 pressure and 120 min of hydrogenation over the Ni/C-500 catalyst, derived from the pyrolysis of Ni-MOFs (Ni : BTC mole ratio of 1.0) at 500 °C for 120 min, which exhibits an average nanoparticle size of ∼14 nm and uniform dispersion, and the highest BET surface area (∼92 m 2 g -1 ) among all investigated Ni/C catalysts. This facilely prepared heterogeneous catalyst would be very promising for the replacement of noble metal catalysts for the efficient catalytic conversion of biomass-derived feedstocks into value-added chemicals.
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Functional Programming with C++ Template Metaprograms
NASA Astrophysics Data System (ADS)
Porkoláb, Zoltán
Template metaprogramming is an emerging new direction of generative programming. With the clever definitions of templates we can force the C++ compiler to execute algorithms at compilation time. Among the application areas of template metaprograms are the expression templates, static interface checking, code optimization with adaption, language embedding and active libraries. However, as template metaprogramming was not an original design goal, the C++ language is not capable of elegant expression of metaprograms. The complicated syntax leads to the creation of code that is hard to write, understand and maintain. Although template metaprogramming has a strong relationship with functional programming, this is not reflected in the language syntax and existing libraries. In this paper we give a short and incomplete introduction to C++ templates and the basics of template metaprogramming. We will enlight the role of template metaprograms, and some important and widely used idioms. We give an overview of the possible application areas as well as debugging and profiling techniques. We suggest a pure functional style programming interface for C++ template metaprograms in the form of embedded Haskell code which is transformed to standard compliant C++ source.
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Lin, Zeming; He, Bingwei; Chen, Jiang; D u, Zhibin; Zheng, Jingyi; Li, Yanqin
2012-08-01
To guide doctors in precisely positioning surgical operation, a new production method of minimally invasive implant guide template was presented. The mandible of patient was scanned by CT scanner, and three-dimensional jaw bone model was constructed based on CT images data The professional dental implant software Simplant was used to simulate the plant based on the three-dimensional CT model to determine the location and depth of implants. In the same time, the dental plaster models were scanned by stereo vision system to build the oral mucosa model. Next, curvature registration technology was used to fuse the oral mucosa model and the CT model, then the designed position of implant in the oral mucosa could be determined. The minimally invasive implant guide template was designed in 3-Matic software according to the design position of implant and the oral mucosa model. Finally, the template was produced by rapid prototyping. The three-dimensional registration technology was useful to fuse the CT data and the dental plaster data, and the template was accurate that could provide the doctors a guidance in the actual planting without cut-off mucosa. The guide template which fabricated by comprehensive utilization of three-dimensional registration, Simplant simulation and rapid prototyping positioning are accurate and can achieve the minimally invasive and accuracy implant surgery, this technique is worthy of clinical use.
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Structural Brain Atlases: Design, Rationale, and Applications in Normal and Pathological Cohorts
Mandal, Pravat K.; Mahajan, Rashima; Dinov, Ivo D.
2015-01-01
Structural magnetic resonance imaging (MRI) provides anatomical information about the brain in healthy as well as in diseased conditions. On the other hand, functional MRI (fMRI) provides information on the brain activity during performance of a specific task. Analysis of fMRI data requires the registration of the data to a reference brain template in order to identify the activated brain regions. Brain templates also find application in other neuroimaging modalities, such as diffusion tensor imaging and multi-voxel spectroscopy. Further, there are certain differences (e.g., brain shape and size) in the brains of populations of different origin and during diseased conditions like in Alzheimer’s disease (AD), population and disease-specific brain templates may be considered crucial for accurate registration and subsequent analysis of fMRI as well as other neuroimaging data. This manuscript provides a comprehensive review of the history, construction and application of brain atlases. A chronological outline of the development of brain template design, starting from the Talairach and Tournoux atlas to the Chinese brain template (to date), along with their respective detailed construction protocols provides the backdrop to this manuscript. The manuscript also provides the automated workflow-based protocol for designing a population-specific brain atlas from structural MRI data using LONI Pipeline graphical workflow environment. We conclude by discussing the scope of brain templates as a research tool and their application in various neuroimaging modalities. PMID:22647262
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Self-Determination Theory and Web-Enhanced Course Template Development
ERIC Educational Resources Information Center
Bachman, Christine M.; Stewart, Cindy
2011-01-01
A theoretical approach to the design and implementation of a web-enhanced course template for Introduction to Psychology is reviewed. Links between psychological constructs and pedagogical principles of learning that are pertinent to a web-based course and the self-determination theory literature are discussed in relation to the design and…
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A study on design and development of enterprise-wide concepts for clinical documentation templates.
Zhou, Li; Gurjar, Rupali; Regier, Rachel; Morgan, Stephen; Meyer, Theresa; Aroy, Teal; Goldman, Debora Scavone; Hongsermeier, Tonya; Middleton, Blackford
2008-11-06
Structured clinical documents are associated with many potential benefits. Underlying terminologies and structure of information are keys to their successful implementation and use. This paper presents a methodology for design and development of enterprise-wide concepts for clinical documentation templates for an ambulatory Electronic Medical Record (EMR) system.
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Bridge, Heather; Smolskis, Mary; Bianchine, Peter; Dixon, Dennis O; Kelly, Grace; Herpin, Betsey; Tavel, Jorge
2009-08-01
A clinical research protocol document must reflect both sound scientific rationale as well as local, national and, when applicable, international regulatory and human subject protections requirements. These requirements originate from a variety of sources, undergo frequent revision and are subject to interpretation. Tools to assist clinical investigators in the production of clinical protocols could facilitate navigating these requirements and ultimately increase the efficiency of clinical research. The National Institute of Allergy and Infectious Diseases (NIAID) developed templates for investigators to serve as the foundation for protocol development. These protocol templates are designed as tools to support investigators in developing clinical protocols. NIAID established a series of working groups to determine how to improve its capacity to conduct clinical research more efficiently and effectively. The Protocol Template Working Group was convened to determine what protocol templates currently existed within NIAID and whether standard NIAID protocol templates should be produced. After review and assessment of existing protocol documents and requirements, the group reached consensus about required and optional content, determined the format and identified methods for distribution as well as education of investigators in the use of these templates. The templates were approved by the NIAID Executive Committee in 2006 and posted as part of the NIAID Clinical Research Toolkit [1] website for broad access. These documents require scheduled revisions to stay current with regulatory and policy changes. The structure of any clinical protocol template, whether comprehensive or specific to a particular study phase, setting or design, affects how it is used by investigators. Each structure presents its own set of advantages and disadvantages. While useful, protocol templates are not stand-alone tools for creating an optimal protocol document, but must be complemented by institutional resources and support. Education and guidance of investigators in the appropriate use of templates is necessary to ensure a complete yet concise protocol document. Due to changing regulatory requirements, clinical protocol templates cannot become static, but require frequent revisions.
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Creating Shape Templates for Patient Specific Biventricular Modeling in Congenital Heart Disease
Gilbert, Kathleen; Farrar, Genevieve; Cowan, Brett R.; Suinesiaputra, Avan; Occleshaw, Christopher; Pontré, Beau; Perry, James; Hegde, Sanjeet; Marsden, Alison; Omens, Jeff; McCulloch, Andrew; Young, Alistair A.
2018-01-01
Survival rates for infants with congenital heart disease (CHD) are improving, resulting in a growing population of adults with CHD. However, the analysis of left and right ventricular function is very time-consuming owing to the variety of congenital morphologies. Efficient customization of patient geometry and function depends on high quality shape templates specifically designed for the application. In this paper, we combine a method for creating finite element shape templates with an interactive template customization to patient MRI examinations. This enables different templates to be chosen depending on patient morphology. To demonstrate this pipeline, a new biventricular template with 162 elements was created and tested in place of an existing 82-element template. The method was able to provide fast interactive biventricular analysis with 0.31 sec per edit response time. The new template was customized to 13 CHD patients with similar biventricular topology, showing improved performance over the previous template and good agreement with clinical indices. PMID:26736353
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Biometric template transformation: a security analysis
NASA Astrophysics Data System (ADS)
Nagar, Abhishek; Nandakumar, Karthik; Jain, Anil K.
2010-01-01
One of the critical steps in designing a secure biometric system is protecting the templates of the users that are stored either in a central database or on smart cards. If a biometric template is compromised, it leads to serious security and privacy threats because unlike passwords, it is not possible for a legitimate user to revoke his biometric identifiers and switch to another set of uncompromised identifiers. One methodology for biometric template protection is the template transformation approach, where the template, consisting of the features extracted from the biometric trait, is transformed using parameters derived from a user specific password or key. Only the transformed template is stored and matching is performed directly in the transformed domain. In this paper, we formally investigate the security strength of template transformation techniques and define six metrics that facilitate a holistic security evaluation. Furthermore, we analyze the security of two wellknown template transformation techniques, namely, Biohashing and cancelable fingerprint templates based on the proposed metrics. Our analysis indicates that both these schemes are vulnerable to intrusion and linkage attacks because it is relatively easy to obtain either a close approximation of the original template (Biohashing) or a pre-image of the transformed template (cancelable fingerprints). We argue that the security strength of template transformation techniques must consider also consider the computational complexity of obtaining a complete pre-image of the transformed template in addition to the complexity of recovering the original biometric template.
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Naklua, Wanpen; Suedee, Roongnapa; Lieberzeit, Peter A
2016-07-15
Molecularly imprinted polymers (MIPs) have been successfully applied as selective materials for assessing the binding activity of agonist and antagonist of dopamine D1 receptor (D1R) by using quartz crystal microbalance (QCM). In this study, D1R derived from rat hypothalamus was used as a template and thus self-organized on stamps. Those were pressed into an oligomer film consisting of acrylic acid: N-vinylpyrrolidone: N,N'-(1,2-dihydroxyethylene) bis-acrylamide in a ratio of 2:3:12 spin coated onto a dual electrode QCM. Such we obtained one D1R-MIP-QCM electrode, whereas the other electrode carried the non-imprinted control polymer (NIP) that had remained untreated. Successful imprinting of D1R was confirmed by AFM. The polymer can re-incorporate D1R leading to frequency responses of 100-1200Hz in a concentration range of 5.9-47.2µM. In a further step such frequency changes proved inherently useful for examining the binding properties of test ligands to D1R. The resulting mass-sensitive measurements revealed Kd of dopamine∙HCl, haloperidol, and (+)-SCH23390 at 0.874, 25.6, and 0.004nM, respectively. These results correlate well with the values determined in radio ligand binding assays. Our experiments revealed that D1R-MIP sensors are useful for estimating the strength of ligand binding to the active single site. Therefore, we have developed a biomimetic surface imprinting strategy for QCM studies of D1R-ligand binding and presented a new method to ligand binding assay for D1R. Copyright © 2016 Elsevier B.V. All rights reserved.
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Identification of endogenous surrogate ligands for human P2Y receptors through an in silico search.
Hiramoto, Takeshi; Nonaka, Yosuke; Inoue, Kazuko; Yamamoto, Takefumi; Omatsu-Kanbe, Mariko; Matsuura, Hiroshi; Gohda, Keigo; Fujita, Norihisa
2004-05-01
G protein-coupled receptors (GPCRs) are distributed widely throughout the human body, and nearly 50% of current medicines act on a GPCR. GPCRs are considered to consist of seven transmembrane alpha-helices that form an alpha-helical bundle in which agonists and antagonists bind. A 3D structure of the target GPCR is indispensable for designing novel medicines acting on a GPCR. We have previously constructed the 3D structure of human P2Y(1) (hP2Y(1)) receptor, a GPCR, by homology modeling with the 3D structure of bovine rhodopsin as a template. In the present study, we have employed an in silico screening for compounds that could bind to the hP2Y(1)-receptor model using AutoDock 3.0. We selected 21 of the 30 top-ranked compounds, and by measuring intracellular Ca(2+) concentration, we identified 12 compounds that activated or blocked the hP2Y(1) receptor stably expressed in recombinant CHO cells. 5-Phosphoribosyl-1-pyrophosphate (PRPP) was found to activate the hP2Y(1) receptor with a low ED(50) value of 15 nM. The Ca(2+) assays showed it had no significant effect on P2Y(2), P2Y(6), or P2X(2) receptors, but acted as a weak agonist on the P2Y(12) receptor. This is the first study to rationally identify surrogate ligands for the P2Y-receptor family.
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Whittington, Christi L; Wojtas, Lukasz; Gao, Wen-Yang; Ma, Shengqian; Larsen, Randy W
2015-03-28
It has now been demonstrated that Ru(ii)tris(2,2'-bipyridine) (RuBpy) can be utilized to template the formation of new metal organic framework (MOF) materials containing crystallographically resolved RuBpy clusters with unique photophysical properties. Two such materials, RWLC-1 and RWLC-2, have now been reported from our laboratory and are composed of RuBpy encapsulated in MOFs composed of Zn(ii) ions and 1,3,5-tris(4-carboxyphenyl)benzene ligands (C. L. Whittington, L. Wojtas and R. W. Larsen, Inorg. Chem., 2014, 53, 160-166). Here, a third RuBpy templated photoactive MOF is described (RWLC-3) that is derived from the reaction between Zn(ii) ions and 1,4-dicarboxybenzene in the presence of RuBpy. Single Crystal X-ray diffraction studies determined the position of RuBpy cations within the crystal lattice. The RWLC-3 structure is described as a 2-fold interpenetrated pillared honeycomb network (bnb) containing crystallographically resolved RuBpy clusters. The two bnb networks are weakly interconnected. The encapsulated RuBpy exhibits two emission decay lifetimes (τ-fast = 120 ns, τ-slow = 453 ns) and a bathochromic shift in the steady state emission spectrum relative to RuBpy in ethanol.
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Formation of target-specific binding sites in enzymes: solid-phase molecular imprinting of HRP.
Czulak, J; Guerreiro, A; Metran, K; Canfarotta, F; Goddard, A; Cowan, R H; Trochimczuk, A W; Piletsky, S
2016-06-07
Here we introduce a new concept for synthesising molecularly imprinted nanoparticles by using proteins as macro-functional monomers. For a proof-of-concept, a model enzyme (HRP) was cross-linked using glutaraldehyde in the presence of glass beads (solid-phase) bearing immobilized templates such as vancomycin and ampicillin. The cross-linking process links together proteins and protein chains, which in the presence of templates leads to the formation of permanent target-specific recognition sites without adverse effects on the enzymatic activity. Unlike complex protein engineering approaches commonly employed to generate affinity proteins, the method proposed can be used to produce protein-based ligands in a short time period using native protein molecules. These affinity materials are potentially useful tools especially for assays since they combine the catalytic properties of enzymes (for signaling) and molecular recognition properties of antibodies. We demonstrate this concept in an ELISA-format assay where HRP imprinted with vancomycin and ampicillin replaced traditional enzyme-antibody conjugates for selective detection of templates at micromolar concentrations. This approach can potentially provide a fast alternative to raising antibodies for targets that do not require high assay sensitivities; it can also find uses as a biochemical research tool, as a possible replacement for immunoperoxidase-conjugates.
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Li, Zheng-Zheng; Yao, Su-Yang; Wu, Jin-Ji; Ye, Bao-Hui
2014-05-30
The reaction of Δ/Λ-[Ru(bpy)2(py)2](2+) with a prochiral sulfide ligand, and then in situ oxidation, provide the corresponding Δ-[Ru(bpy)2{(R)-OSO-iPr}](+) and Λ-[Ru(bpy)2{(S)-OSO-iPr}](+) (OSO-iPr = 2-isopropylsulfonylbenzonate) enantiomers in a yield of 83% with 98% ee. The chiral sulfoxides were obtained by treatment of the sulfoxide complexes with TFA in a yield of 90% with 88-91% ee.
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Williams, W Robert
2011-01-01
Purine nucleotides play a central role in signal transduction events initiated at the cell membrane. The NO-cGMP-cGK pathway, in particular, mediates events involving NOS and some classes of K(+) ion channel. The aim of this study is to investigate relative molecular similarity within the ligands binding to NOS, K(ATP), BK(Ca) channels and regulatory nucleotides. Minimum energy conformers of the ligand structures were superimposed and fitted to L-arginine and the nucleotides of adenine and guanine using a computational program. Distinctive patterns were evident in the fitting of NOS isoform antagonists to L-arginine. K(ATP) channel openers and antagonists superimposed on the glycosidic linkage and imidazole ring of the purine nucleotides, and guanidinium and ribose groups of GTP in the case of glibenclamide. The fits of BK(Ca) channel openers and antagonists to cGMP were characterized by the linear dimensions of their structures; distances between terminal oxy groups in respect of dexamethasone and aldosterone. The findings provide structural evidence for the functional interaction between K(+) channel openers/antagonists and the regulatory nucleotides. Use of the purine nucleotide template systematizes the considerable heterogeneity evident within the structures of ligands operating on K(+) ion channels. © 2010 The Author. JPP © 2010 Royal Pharmaceutical Society.
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Exploration of N-arylpiperazine Binding Sites of D2 Dopaminergic Receptor.
Soskic, Vukic; Sukalovic, Vladimir; Kostic-Rajacic, Sladjana
2015-01-01
The crystal structures of the D3 dopamine receptor and several other G-protein coupled receptors (GPCRs) were published in recent times. Those 3D structures are used by us and other scientists as a template for the homology modeling and ligand docking analysis of related GPCRs. Our main scientific interest lies in the field of pharmacologically active N-arylpiperazines that exhibit antipsychotic and/or antidepressant properties, and as such are dopaminergic and serotonergic receptor ligands. In this short review article we are presenting synthesis and biological data on the new N-arylpipereazine as well our results on molecular modeling of the interactions of those N-arylpiperazines with the model of D2 dopamine receptors. To obtain that model the crystal structure of the D3 dopamine receptor was used. Our results show that the N-arylpiperazines binding site consists of two pockets: one is the orthosteric binding site where the N-arylpiperazine part of the ligand is docked and the second is a non-canonical accessory binding site for N-arylpipereazine that is formed by a second extracellular loop (ecl2) of the receptor. Until now, the structure of this receptor region was unresolved in crystal structure analyses of the D3 dopamine receptor. To get a more complete picture of the ligand - receptor interaction, DFT quantum mechanical calculations on N-arylpiperazine were performed and the obtained models were used to examine those interactions.
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Paul, Noel M.; Taylor, Michelle; Kumar, Rakesh; Deschamps, Jeffrey R.; Luedtke, Robert R.; Newman, Amy Hauck
2011-01-01
Discovering dopamine D2-like receptor subtype-selective ligands has been a focus of significant investigation. The D2R-selective antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidinyl]methylindole (1, L741,626; Ki(D2R/D3R) = 11.2:163 nM) has previously provided a lead template for chemical modification. Herein, analogues have been synthesized where the piperidine was replaced by a tropane ring that reversed the selectivity seen in the parent compound, in human hD2LR- or hD3R-transfected HEK 293 cells (31, Ki(D2R/D3R) = 33.4: 15.5 nM). Further exploration of both N-substituted and aryl ring-substituted analogues resulted in the discovery of several high affinity D2R/D3R ligands with 3-benzofurylmethyl-substituents (e.g., 45, Ki(D2R/D3R) = 1.7:0.34 nM) that induced high affinity not achieved in similarly N-substituted piperidine analogues and significantly (470-fold) improved D3R binding affinity compared to the parent ligand 1. X-ray crystallographic data revealed a distinctive spatial arrangement of pharmacophoric elements in the piperidinol vs tropine analogues, providing clues for the diversity in SAR at the D2 and D3 receptor subtypes. PMID:18774793
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Design, fabrication, and integration testing of the Garden Banks 388 subsea production template
DOE Office of Scientific and Technical Information (OSTI.GOV)
Ledbetter, W.R.; Smith, D.W.; Pierce, D.M.
1995-12-31
Enserch Exploration`s Garden Banks 388 development has a production scheme based around a floating drilling and production facility and subsea drilling/production template. The Floating Production Facility (FPF) is a converted semisubmersible drilling rig that will drill and produce through a 24-well slot subsea template. This development is located in Block 388 of the Garden Banks area in the Gulf of Mexico approximately 200 miles southwest of New Orleans, Louisiana. The production system is being installed in an area of known oil and gas reserves and will produce to a shallow water platform 54 miles away at Eugene Island 315. Themore » FPF will be permanently moored above the template. The subsea template has been installed in 2190 feet of water and will produce through a 2,000 foot free-standing production riser system to the FPF. The produced fluids are partially separated on the FPF before oil and gas are pumped through the template to export gathering lines that are connected to the shallow water facility. The system designed through-put is 40,000 BOPD of oil and 120 MMSCFD of gas.« less
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Template identification technology of nuclear warheads and components
NASA Astrophysics Data System (ADS)
Liu, Su-Ping; Gong, Jian; Hao, Fan-Hua; Hu, Guang-Chun
2008-02-01
Template identification technology (TIT) is designed for the scenarios where a batch of disarmed nuclear weapons or components would be dismantled to observe a nuclear disarmament treaty. The core function played by the TIT is to make a judgment on whether the verified item belongs to a certain kind of nuclear weapons or component (NW/NC) or to which kind the verified item belongs. This paper analyses the functions played by the TIT in the process of NW/NC dismantlement, and proposes that two phases would be followed when applying the TIT: firstly to establish NW/NC templates with a sample of size n drawn from a certain kind of disarmament NW; secondly to authenticate NW/NC by means of the TIT. This paper also expatiates some terms related to the concept of the TIT and investigates on the development status of NW/NC TIT based on radiation signatures. The study concludes that the design of template structure is crucial to the establishment of an effective TIT and that starting from different research angles and aiming at the same goal of classification different template structures and corresponding template identification methods can be built up to meet specific identification requirements.
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Das, Mohua; Tianming, Yang; Jinghua, Dong; Prasetya, Fransisca; Yiming, Xie; Wong, Kendra; Cheong, Adeline; Woon, Esther C Y
2018-06-19
Dynamic combinatorial chemistry (DCC) is a powerful supramolecular approach for discovering ligands for biomolecules. To date, most, if not all, biologically-templated DCC employ only a single biomolecule in directing the self-assembly process. To expand the scope and potential of DCC, herein, we developed a novel multi-protein DCC strategy which combines the discriminatory power of zwitterionic 'thermal-tag' with the sensitivity of differential scanning fluorimetry. This strategy enables the discovery of ligands against several proteins of interest concurrently. It is remarkably sensitive and could differentiate the binding of ligands to structurally-similar subfamily members, which is extremely challenging to achieve. Through this approach, we were able to simultaneously identify subfamily-selective probes against two clinically important epigenetic enzymes, FTO (7; IC₅₀ = 2.6 µM) and ALKBH3 (8; IC₅₀ = 3.7 µM). To our knowledge, this is the first report of a subfamily-selective ALKBH3 inhibitor. The developed strategy could, in principle, be adapted to a broad range of proteins, thus it shall be of widespread scientific interest. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Engle, Keary M.; Yu, Jin-Quan
2013-01-01
Homogeneous transition metal–catalyzed reactions are indispensable to all facets of modern chemical synthesis. It is thus difficult to imagine that for much of the early 20th century, the reactivity and selectivity of all known homogeneous metal catalysts paled in comparison to their heterogeneous and biological counterparts. In the intervening decades, advances in ligand design bridged this divide, such that today some of the most demanding bond-forming events are mediated by ligand-supported homogeneous metal species. While ligand design has propelled many areas of homogeneous catalysis, in the field of Pd(II)-catalyzed C–H functionalization, suitable ligand scaffolds are lacking, which has hampered the development of broadly practical transformations based on C–H functionalization logic. In this review, we offer an account of our research employing three ligand scaffolds, mono-N-protected amino acids, 2,6-disubstituted pyridines, and 2,2′-bipyridines, to address challenges posed by several synthetically versatile substrate classes. Drawing on this work, we discuss principles of ligand design, such as the need to match a ligand to a particular substrate class, and how ligand traits such as tunability and modularity can be advantageous in reaction discovery. PMID:23565982
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Sample transportation management plans and templates.
DOT National Transportation Integrated Search
2010-08-01
This Guide consisting of samples, templates, and tips is designed to help transportation agencies with the : development and implementation of their own Transportation Management Plans (TMPs). Understanding : the work zone impacts is critical to deve...
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Design of multi-phase dynamic chemical networks
NASA Astrophysics Data System (ADS)
Chen, Chenrui; Tan, Junjun; Hsieh, Ming-Chien; Pan, Ting; Goodwin, Jay T.; Mehta, Anil K.; Grover, Martha A.; Lynn, David G.
2017-08-01
Template-directed polymerization reactions enable the accurate storage and processing of nature's biopolymer information. This mutualistic relationship of nucleic acids and proteins, a network known as life's central dogma, is now marvellously complex, and the progressive steps necessary for creating the initial sequence and chain-length-specific polymer templates are lost to time. Here we design and construct dynamic polymerization networks that exploit metastable prion cross-β phases. Mixed-phase environments have been used for constructing synthetic polymers, but these dynamic phases emerge naturally from the growing peptide oligomers and create environments suitable both to nucleate assembly and select for ordered templates. The resulting templates direct the amplification of a phase containing only chain-length-specific peptide-like oligomers. Such multi-phase biopolymer dynamics reveal pathways for the emergence, self-selection and amplification of chain-length- and possibly sequence-specific biopolymers.
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3D-printed guiding templates for improved osteosarcoma resection
NASA Astrophysics Data System (ADS)
Ma, Limin; Zhou, Ye; Zhu, Ye; Lin, Zefeng; Wang, Yingjun; Zhang, Yu; Xia, Hong; Mao, Chuanbin
2016-03-01
Osteosarcoma resection is challenging due to the variable location of tumors and their proximity with surrounding tissues. It also carries a high risk of postoperative complications. To overcome the challenge in precise osteosarcoma resection, computer-aided design (CAD) was used to design patient-specific guiding templates for osteosarcoma resection on the basis of the computer tomography (CT) scan and magnetic resonance imaging (MRI) of the osteosarcoma of human patients. Then 3D printing technique was used to fabricate the guiding templates. The guiding templates were used to guide the osteosarcoma surgery, leading to more precise resection of the tumorous bone and the implantation of the bone implants, less blood loss, shorter operation time and reduced radiation exposure during the operation. Follow-up studies show that the patients recovered well to reach a mean Musculoskeletal Tumor Society score of 27.125.
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Chae, Michael P; Hunter-Smith, David J; Rostek, Marie; Smith, Julian A; Rozen, Warren Matthew
2018-01-01
Optimizing preoperative planning is widely sought in deep inferior epigastric artery perforator (DIEP) flap surgery. One reason for this is that rates of fat necrosis remain relatively high (up to 35%), and that adjusting flap design by an improved understanding of individual perforasomes and perfusion characteristics may be useful in reducing the risk of fat necrosis. Imaging techniques have substantially improved over the past decade, and with recent advances in 3D printing, an improved demonstration of imaged anatomy has become available. We describe a 3D-printed template that can be used preoperatively to mark out a patient's individualized perforasome for flap planning in DIEP flap surgery. We describe this "perforasome template" technique in a case of a 46-year-old woman undergoing immediate unilateral breast reconstruction with a DIEP flap. Routine preoperative computed tomographic angiography was performed, with open-source software (3D Slicer, Autodesk MeshMixer and Cura) and a desktop 3D printer (Ultimaker 3E) used to create a template used to mark intra-flap, subcutaneous branches of deep inferior epigastric artery (DIEA) perforators on the abdomen. An individualized 3D printed template was used to estimate the size and boundaries of a perforasome and perfusion map. The information was used to aid flap design. We describe a new technique of 3D printing a patient-specific perforasome template that can be used preoperatively to infer perforasomes and aid flap design.
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Parmaksızoğlu, Selami; Alçı, Mustafa
2011-01-01
Cellular Neural Networks (CNNs) have been widely used recently in applications such as edge detection, noise reduction and object detection, which are among the main computer imaging processes. They can also be realized as hardware based imaging sensors. The fact that hardware CNN models produce robust and effective results has attracted the attention of researchers using these structures within image sensors. Realization of desired CNN behavior such as edge detection can be achieved by correctly setting a cloning template without changing the structure of the CNN. To achieve different behaviors effectively, designing a cloning template is one of the most important research topics in this field. In this study, the edge detecting process that is used as a preliminary process for segmentation, identification and coding applications is conducted by using CNN structures. In order to design the cloning template of goal-oriented CNN architecture, an Artificial Bee Colony (ABC) algorithm which is inspired from the foraging behavior of honeybees is used and the performance analysis of ABC for this application is examined with multiple runs. The CNN template generated by the ABC algorithm is tested by using artificial and real test images. The results are subjectively and quantitatively compared with well-known classical edge detection methods, and other CNN based edge detector cloning templates available in the imaging literature. The results show that the proposed method is more successful than other methods.
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Parmaksızoğlu, Selami; Alçı, Mustafa
2011-01-01
Cellular Neural Networks (CNNs) have been widely used recently in applications such as edge detection, noise reduction and object detection, which are among the main computer imaging processes. They can also be realized as hardware based imaging sensors. The fact that hardware CNN models produce robust and effective results has attracted the attention of researchers using these structures within image sensors. Realization of desired CNN behavior such as edge detection can be achieved by correctly setting a cloning template without changing the structure of the CNN. To achieve different behaviors effectively, designing a cloning template is one of the most important research topics in this field. In this study, the edge detecting process that is used as a preliminary process for segmentation, identification and coding applications is conducted by using CNN structures. In order to design the cloning template of goal-oriented CNN architecture, an Artificial Bee Colony (ABC) algorithm which is inspired from the foraging behavior of honeybees is used and the performance analysis of ABC for this application is examined with multiple runs. The CNN template generated by the ABC algorithm is tested by using artificial and real test images. The results are subjectively and quantitatively compared with well-known classical edge detection methods, and other CNN based edge detector cloning templates available in the imaging literature. The results show that the proposed method is more successful than other methods. PMID:22163903
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Zhang, Qiong; Tian, Xiaohe; Zhou, Hongping; Wu, Jieying; Tian, Yupeng
2017-01-01
The application of two-photon absorption (2PA) materials is a classical research field and has recently attracted increasing interest. It has generated a demand for new dyes with high 2PA cross-sections. In this short review, we briefly cover the structure-2PA property relationships of organic fluorophores, organic-inorganic nanohybrids and metal complexes explored by our group. (1) The two-photon absorption cross-section (δ) of organic fluorophores increases with the extent of charge transfer, which is important to optimize the core, donor-acceptor pair, and conjugation-bridge to obtain a large δ value. Among the various cores, triphenylamine appears to be an efficient core. Lengthening of the conjugation with styryl groups in the D-π-D quadrupoles and D-π-A dipoles increased δ over a long wavelength range than when vinylene groups were used. Large values of δ were observed for extended conjugation length and moderate donor-acceptors in the near-IR wavelengths. The δ value of the three-arm octupole is larger than that of the individual arm, if the core has electron accepting groups that allow significant electronic coupling between the arms; (2) Optical functional organic/inorganic hybrid materials usually show high thermal stability and excellent optical activity; therefore the design of functional organic molecules to build functional organic-inorganic hybrids and optimize the 2PA properties are significant. Advances have been made in the design of organic-inorganic nanohybrid materials of different sizes and shapes for 2PA property, which provide useful examples to illustrate the new features of the 2PA response in comparison to the more thoroughly investigated donor-acceptor based organic compounds and inorganic components; (3) Metal complexes are of particular interest for the design of new materials with large 2PA ability. They offer a wide range of metals with different ligands, which can give rise to tunable electronic and 2PA properties. The metal ions, including transition metals and lanthanides, can serve as an important part of the structure to control the intramolecular charge-transfer process that drives the 2PA process. As templates, transition metal ions can assemble simple to more sophisticated ligands in a variety of multipolar arrangements resulting in interesting and tailorable electronic and optical properties, depending on the nature of the metal center and the energetics of the metal-ligand interactions, such as intraligand charge-transfer (ILCT) and metal-ligand charge-transfer (MLCT) processes. Lanthanide complexes are attractive for a number of reasons: (i) their visible emissions are quite long-lived; (ii) their absorption and emission can be tuned with the aid of appropriate photoactive ligands; (iii) the accessible energy-transfer path between the photo-active ligands and the lanthanide ion can facilitate efficient lanthanide-based 2PA properties. Thus, the above materials with excellent 2PA properties should be applied in two-photon applications, especially two-photon fluorescence microscopy (TPFM) and related emission-based applications. Furthermore, the progress of research into the use of those new 2PA materials with moderate 2PA cross section in the near-infrared region, good biocompatibility, and enhanced two-photon excited fluorescence for two-photon bio-imaging is summarized. In addition, several possible future directions in this field are also discussed (146 references). PMID:28772584
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Talley, Todd T.; Harel, Michal; Hibbs, Ryan E.; Radić, Zoran; Tomizawa, Motohiro; Casida, John E.; Taylor, Palmer
2008-01-01
Acetylcholine-binding proteins (AChBPs) from mollusks are suitable structural and functional surrogates of the nicotinic acetylcholine receptors when combined with transmembrane spans of the nicotinic receptor. These proteins assemble as a pentamer with identical ACh binding sites at the subunit interfaces and show ligand specificities resembling those of the nicotinic receptor for agonists and antagonists. A subset of ligands, termed the neonicotinoids, exhibit specificity for insect nicotinic receptors and selective toxicity as insecticides. AChBPs are of neither mammalian nor insect origin and exhibit a distinctive pattern of selectivity for the neonicotinoid ligands. We define here the binding orientation and determinants of differential molecular recognition for the neonicotinoids and classical nicotinoids by estimates of kinetic and equilibrium binding parameters and crystallographic analysis. Neonicotinoid complex formation is rapid and accompanied by quenching of the AChBP tryptophan fluorescence. Comparisons of the neonicotinoids imidacloprid and thiacloprid in the binding site from Aplysia californica AChBP at 2.48 and 1.94 Å in resolution reveal a single conformation of the bound ligands with four of the five sites occupied in the pentameric crystal structure. The neonicotinoid electronegative pharmacophore is nestled in an inverted direction compared with the nicotinoid cationic functionality at the subunit interfacial binding pocket. Characteristic of several agonists, loop C largely envelops the ligand, positioning aromatic side chains to interact optimally with conjugated and hydrophobic regions of the neonicotinoid. This template defines the association of interacting amino acids and their energetic contributions to the distinctive interactions of neonicotinoids. PMID:18477694
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Rational computational design for the development of andrographolide molecularly imprinted polymer
NASA Astrophysics Data System (ADS)
Krishnan, Hemavathi; Islam, K. M. Shafiqul; Hamzah, Zainab; Ahmad, Mohd Noor
2017-10-01
Andrographolide is a popular medicinal compound derived from Andrographis Paniculata (AP). Molecularly Imprint Polymer (MIP) is a "Lock and Key" approach, where MIP is the lock and Andrographolide is the key which fits to the MIP lock by both physically and chemically. MIP will be used as selective extraction tool to enrich Andrographolide bioactive compound. Pre-polymerization step is crucial to design MIP. This work investigates molecular interactions and the Gibbs free binding energies on the development of MIP. The structure of Andrographolide (template) and functional monomers were drawn in HyperChem 8.0.10. A hybrid quantum chemical model was used with a few functional monomers. Possible conformations of template and functional monomer as 1:n (n < 4) were designed and simulated to geometrically optimize the complex to the lowest energy in gas phase. The Gibbs free binding energies of each conformation were calculated using semi-empirical PM3 simulation method. Results proved that functional monomers that contain carboxylic group shows higher binding energy compared to those with amine functional group. Itaconic acid (IA) chosen as the best functional monomer at optimum ratio (1:3) of template: monomer to prepare andrographolide MIP. This study demonstrates the importance of studying intermolecular interaction among template, functional monomer and template-monomer ratio in developing MIP.
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Template for success: using a resident-designed sign-out template in the handover of patient care.
Clark, Clancy J; Sindell, Sarah L; Koehler, Richard P
2011-01-01
Report our implementation of a standardized handover process in a general surgery residency program. The standardized handover process, sign-out template, method of implementation, and continuous quality improvement process were designed by general surgery residents with support of faculty and senior hospital administration using standard work principles and business models of the Virginia Mason Production System and the Toyota Production System. Nonprofit, tertiary referral teaching hospital. General surgery residents, residency faculty, patient care providers, and hospital administration. After instruction in quality improvement initiatives, a team of general surgery residents designed a sign-out process using an electronic template and standard procedures. The initial implementation phase resulted in 73% compliance. Using resident-driven continuous quality improvement processes, real-time feedback enabled residents to modify and improve this process, eventually attaining 100% compliance and acceptance by residents. The creation of a standardized template and protocol for patient handovers might eliminate communication failures. Encouraging residents to participate in this process can establish the groundwork for successful implementation of a standardized handover process. Integrating a continuous quality-improvement process into such an initiative can promote active participation of busy general surgery residents and lead to successful implementation of standard procedures. Copyright © 2011 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.
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Lowekamp, Bradley C; Chen, David T; Ibáñez, Luis; Blezek, Daniel
2013-01-01
SimpleITK is a new interface to the Insight Segmentation and Registration Toolkit (ITK) designed to facilitate rapid prototyping, education and scientific activities via high level programming languages. ITK is a templated C++ library of image processing algorithms and frameworks for biomedical and other applications, and it was designed to be generic, flexible and extensible. Initially, ITK provided a direct wrapping interface to languages such as Python and Tcl through the WrapITK system. Unlike WrapITK, which exposed ITK's complex templated interface, SimpleITK was designed to provide an easy to use and simplified interface to ITK's algorithms. It includes procedural methods, hides ITK's demand driven pipeline, and provides a template-less layer. Also SimpleITK provides practical conveniences such as binary distribution packages and overloaded operators. Our user-friendly design goals dictated a departure from the direct interface wrapping approach of WrapITK, toward a new facade class structure that only exposes the required functionality, hiding ITK's extensive template use. Internally SimpleITK utilizes a manual description of each filter with code-generation and advanced C++ meta-programming to provide the higher-level interface, bringing the capabilities of ITK to a wider audience. SimpleITK is licensed as open source software library under the Apache License Version 2.0 and more information about downloading it can be found at http://www.simpleitk.org.
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Jupp, Simon; Burdett, Tony; Welter, Danielle; Sarntivijai, Sirarat; Parkinson, Helen; Malone, James
2016-01-01
Authoring bio-ontologies is a task that has traditionally been undertaken by skilled experts trained in understanding complex languages such as the Web Ontology Language (OWL), in tools designed for such experts. As requests for new terms are made, the need for expert ontologists represents a bottleneck in the development process. Furthermore, the ability to rigorously enforce ontology design patterns in large, collaboratively developed ontologies is difficult with existing ontology authoring software. We present Webulous, an application suite for supporting ontology creation by design patterns. Webulous provides infrastructure to specify templates for populating ontology design patterns that get transformed into OWL assertions in a target ontology. Webulous provides programmatic access to the template server and a client application has been developed for Google Sheets that allows templates to be loaded, populated and resubmitted to the Webulous server for processing. The development and delivery of ontologies to the community requires software support that goes beyond the ontology editor. Building ontologies by design patterns and providing simple mechanisms for the addition of new content helps reduce the overall cost and effort required to develop an ontology. The Webulous system provides support for this process and is used as part of the development of several ontologies at the European Bioinformatics Institute.
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40 CFR Appendix C to Subpart Nnn... - Method for the Determination of Product Density
Code of Federal Regulations, 2013 CFR
2013-07-01
... One square foot (12 in. by 12 in.) template, or templates that are multiples of one square foot, for... to the plant's written procedure for the designated product. 3.2Cut samples using one square foot (or multiples of one square foot) template. 3.3Weigh product and obtain area weight (lb/ft2). 3.4Measure sample...
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40 CFR Appendix C to Subpart Nnn... - Method for the Determination of Product Density
Code of Federal Regulations, 2014 CFR
2014-07-01
... One square foot (12 in. by 12 in.) template, or templates that are multiples of one square foot, for... to the plant's written procedure for the designated product. 3.2Cut samples using one square foot (or multiples of one square foot) template. 3.3Weigh product and obtain area weight (lb/ft2). 3.4Measure sample...
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NASA Astrophysics Data System (ADS)
Parambil, Jose V.; Poornachary, Sendhil K.; Tan, Reginald B. H.; Heng, Jerry Y. Y.
2017-07-01
Studies on the use of template surfaces to induce heterogeneous crystal nucleation have gained momentum in recent years-with potential applications in selective crystallisation of polymorphs and in the generation of seed crystals in a continuous crystallisation process. In developing a template-assisted solution crystallisation process, the kinetics of homogeneous versus heterogeneous crystal nucleation could be influenced by solute-solvent, solute-template, and solvent-template interactions. In this study, we report the effect of solvents of varying polarity on the nucleation of carbamazepine (CBZ) crystal polymorphs, a model active pharmaceutical ingredient. The experimental results demonstrate that functionalised template surfaces are effective in promoting crystallisation of either the metastable (form II) or stable (form III) polymorphs of CBZ only in moderately (methanol, ethanol, isopropanol) and low polar (toluene) solvents. A solvent with high polarity (acetonitrile) is thought to mask the template effect on heterogeneous nucleation due to strong solute-solvent and solvent-template interactions. The current study highlights that a quality-by-design (QbD) approach-considering the synergistic effects of solute concentration, solvent type, solution temperature, and template surface chemistry on crystal nucleation-is critical to the development of a template-induced crystallisation process.
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Development of highly porous crystalline titania photocatalysts
NASA Astrophysics Data System (ADS)
Marszewski, Michal
The objectives of this dissertation are the design, synthesis, and characterization of titania materials with surface area, porosity, crystallinity and doping tailored toward photocatalytic applications. Ultimately, the research should result in a strategy allowing the synthesis of titania with all these important features. The synthetic methods investigated in this research will include: i) soft-templating, ii) hard-templating, and iii) modified precursor strategy. Soft-templating strategy uses organic templates--either block copolymers or surfactants--that under specific conditions assemble into micelles, and later, these micelles are used to template the desired material around them. The resulting organic-inorganic composite is then calcined in air to remove the organic template and recover the final material with high surface area and large pore volume. This work explores 1) synthesis of titania materials in the presence of polymer templates, and the effects of different synthetic conditions on the structure of the resulting materials. Hard-templating, in contrast to soft-templating, uses inorganic templates. The hard template is introduced during the synthesis to cast its shape onto the fabricated material and removed afterwards, when the material has formed. The final material is an inverse replica of the hard template used, typically with a well-developed mesostructure. This work explores 1) hard templating synthesis of titania materials using silica and alumina, and 2) the effects of the template amount and type. The modified precursor strategy is a novel synthetic method, developed in this research, and designed specifically to achieve titania material with high surface area, large pore volume, high crystallinity, and possibly doping. The modified precursors are prepared by reacting generic titania precursors, such as titanium isopropoxide (TIPO), with organic acids, which results in substitution of some or all alkoxide groups in TIPO structure. The goal is to introduce new, easily carbonizable groups in TIPO structure so that the modified precursor can serve as titania and carbon precursor simultaneously. Subsequently, during carbonization in inert atmosphere, a carbon framework is formed that works as a scaffold, protecting titania during its crystallization. Afterwards, the carbon scaffold is removed by calcination in air. This work explores the modified precursor strategy by 1) preparing titania materials from TIPO modified with different carboxylic acids and 2) investigating the effect of the modifying acid on the properties of the carbon-titania composites and the final titania materials.
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Conformational Transitions upon Ligand Binding: Holo-Structure Prediction from Apo Conformations
Seeliger, Daniel; de Groot, Bert L.
2010-01-01
Biological function of proteins is frequently associated with the formation of complexes with small-molecule ligands. Experimental structure determination of such complexes at atomic resolution, however, can be time-consuming and costly. Computational methods for structure prediction of protein/ligand complexes, particularly docking, are as yet restricted by their limited consideration of receptor flexibility, rendering them not applicable for predicting protein/ligand complexes if large conformational changes of the receptor upon ligand binding are involved. Accurate receptor models in the ligand-bound state (holo structures), however, are a prerequisite for successful structure-based drug design. Hence, if only an unbound (apo) structure is available distinct from the ligand-bound conformation, structure-based drug design is severely limited. We present a method to predict the structure of protein/ligand complexes based solely on the apo structure, the ligand and the radius of gyration of the holo structure. The method is applied to ten cases in which proteins undergo structural rearrangements of up to 7.1 Å backbone RMSD upon ligand binding. In all cases, receptor models within 1.6 Å backbone RMSD to the target were predicted and close-to-native ligand binding poses were obtained for 8 of 10 cases in the top-ranked complex models. A protocol is presented that is expected to enable structure modeling of protein/ligand complexes and structure-based drug design for cases where crystal structures of ligand-bound conformations are not available. PMID:20066034
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Templating Influence of Molecular Precursors on Pr(OH)3 Nanostructures.
Hemmer, Eva; Cavelius, Christian; Huch, Volker; Mathur, Sanjay
2015-07-06
Four new praseodymium alkoxo and amido compounds ([Pr3(μ3-OtBu)2(μ2-OtBu)3(OtBu)4(HOtBu)2] (1), [Pr{OC(tBu)3}3(THF)] (2), [PrCl{N(SiMe3)2}2(THF)]2 (3), and [PrCl{OC(tBu)3}2(THF)]2 (4)) were synthesized and structurally characterized by single-crystal X-ray diffraction analysis. Application of these compounds in solvothermal synthesis of praseodymium oxide/hydroxide nanostructures showed their templating influence on the morphology and phase composition of the resulting solid-state materials. Differential reactivity of the chosen alkoxide ligands toward water and the different arrangements of metal-oxygen units in the studied precursor compounds strongly influenced the kinetics of hydrolysis and cross-condensation reactions as manifested in the morphological changes and phase composition of the final products. Thermal decomposition studies of 1-4 confirmed their conversion into the corresponding oxide phases. Activation of compounds 1, 2, and 4 by either a base or a stoichiometric amount of water showed the distinct influence of their chemical configuration on the obtained nanopowders: whereas 1 solely produced nanorods of Pr(OH)3, 2 predominantly formed a mixture of rod-shaped and spherical particles. The solvothermal decomposition of 4 resulted in Pr(OH)2Cl or PrOCl due to the presence of Cl ligands in the molecular precursor. The resultant materials were thoroughly characterized to demonstrate the relationship between precursor chemistry and the processing parameters that are clearly manifested in the morphology and phase of the final ceramics.
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Computational approaches for drug discovery.
Hung, Che-Lun; Chen, Chi-Chun
2014-09-01
Cellular proteins are the mediators of multiple organism functions being involved in physiological mechanisms and disease. By discovering lead compounds that affect the function of target proteins, the target diseases or physiological mechanisms can be modulated. Based on knowledge of the ligand-receptor interaction, the chemical structures of leads can be modified to improve efficacy, selectivity and reduce side effects. One rational drug design technology, which enables drug discovery based on knowledge of target structures, functional properties and mechanisms, is computer-aided drug design (CADD). The application of CADD can be cost-effective using experiments to compare predicted and actual drug activity, the results from which can used iteratively to improve compound properties. The two major CADD-based approaches are structure-based drug design, where protein structures are required, and ligand-based drug design, where ligand and ligand activities can be used to design compounds interacting with the protein structure. Approaches in structure-based drug design include docking, de novo design, fragment-based drug discovery and structure-based pharmacophore modeling. Approaches in ligand-based drug design include quantitative structure-affinity relationship and pharmacophore modeling based on ligand properties. Based on whether the structure of the receptor and its interaction with the ligand are known, different design strategies can be seed. After lead compounds are generated, the rule of five can be used to assess whether these have drug-like properties. Several quality validation methods, such as cost function analysis, Fisher's cross-validation analysis and goodness of hit test, can be used to estimate the metrics of different drug design strategies. To further improve CADD performance, multi-computers and graphics processing units may be applied to reduce costs. © 2014 Wiley Periodicals, Inc.
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Zhou, Jiayu; Pan, Bo; Yang, Qinghua; Zhao, Yanyong; He, Leren; Lin, Lin; Sun, Hengyun; Song, Yupeng; Yu, Xiaobo; Sun, Zhongyang; Jiang, Haiyue
2016-10-01
During microtia reconstruction, the intraoperative design of the cartilage framework is important for the appearance and symmetry of the bilateral auricles. Templates (traditionally, the X-ray film template) are usually utilized to complete the task, which can provide cues regarding size, cranioauricular angle and positioning to the surgeons. With a combination of three-dimensional (3D) scanning and additive manufacturing (AM) techniques, we utilized two different ear-shaped templates (sheet moulding and 3D templates) during the fabrication of 3D-customized autologous cartilage frameworks for auricle reconstruction. Forty unilateral microtia patients were included in the study. All the patients underwent auricle reconstruction using the tissue-expanding technique assisted by the new AM templates. Images were processed using computer-aided design software and exported to print two different AM ear-shaped templates: sheet moulding and 3D. Both templates were assisted by the 3D framework fabrication. The 3D images of each patient's head were captured preoperatively using a 3D scanner. X-ray film templates were also made for the patients. The lengths and widths of the contralateral auricles, X-ray film and sheet moulding templates were measured in triplicate. The error of the template and the contralateral auricle were used to compare the accuracy between the two templates. Between January and May 2014, 40 unilateral microtia patients aged 6-29 years were included in this study. All patients underwent auricle reconstruction using autogenous costal cartilage. The sterilized AM templates were used to assist in the framework fabrication. The operative time was decreased by an average of 15 min compared with the method assisted by the X-ray film template. Postoperative appearance evaluation (based on five indexes: symmetry, length, width, cranioauricular angle and the substructure of the reconstructed ear) was performed by both the doctors and the patients (or their parents). Follow-up (ranging from 9 to 18 months) showed that all of the patients obtained satisfactory results with life-like 3D configuration and symmetric cranioauricular angle. The follow-up showed that no surgery-related complications occurred. Comparing the accuracy of the X-ray film and sheet moulding templates, the average errors of length were 1.8 mm ± 1.44 mm and 0.39 mm ± 0.35 mm, respectively, and the average width errors were 1.32 mm ± 0.88 mm and 0.3 mm ± 0.47 mm, respectively. The new sheet moulding template was more accurate than the X-ray template. The new sheet-moulding template is much more accurate than the traditional X-ray film template. Framework fabrication assisted by accurate 3D and informative AM templates contributed to individualized cartilage framework fabrication and satisfactory results. Copyright © 2016 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
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Development of Total Knee Replacement Digital Templating Software
NASA Astrophysics Data System (ADS)
Yusof, Siti Fairuz; Sulaiman, Riza; Thian Seng, Lee; Mohd. Kassim, Abdul Yazid; Abdullah, Suhail; Yusof, Shahril; Omar, Masbah; Abdul Hamid, Hamzaini
In this study, by taking full advantage of digital X-ray and computer technology, we have developed a semi-automated procedure to template knee implants, by making use of digital templating method. Using this approach, a software system called OrthoKneeTMhas been designed and developed. The system is to be utilities as a study in the Department of Orthopaedic and Traumatology in medical faculty, UKM (FPUKM). OrthoKneeTMtemplating process employs uses a technique similar to those used by many surgeons, using acetate templates over X-ray films. Using template technique makes it easy to template various implant from every Implant manufacturers who have with a comprehensive database of templates. The templating functionality includes, template (knee) and manufactures templates (Smith & Nephew; and Zimmer). From an image of patient x-ray OrthoKneeTMtemplates help in quickly and easily reads to the approximate template size needed. The visual templating features then allow us quickly review multiple template sizes against the X-ray and thus obtain the nearly precise view of the implant size required. The system can assist by templating on one patient image and will generate reports that can accompany patient notes. The software system was implemented in Visual basic 6.0 Pro using the object-oriented techniques to manage the graphics and objects. The approaches for image scaling will be discussed. Several of measurement in orthopedic diagnosis process have been studied and added in this software as measurement tools features using mathematic theorem and equations. The study compared the results of the semi-automated (using digital templating) method to the conventional method to demonstrate the accuracy of the system.
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Ligand binding by repeat proteins: natural and designed
Grove, Tijana Z; Cortajarena, Aitziber L; Regan, Lynne
2012-01-01
Repeat proteins contain tandem arrays of small structural motifs. As a consequence of this architecture, they adopt non-globular, extended structures that present large, highly specific surfaces for ligand binding. Here we discuss recent advances toward understanding the functional role of this unique modular architecture. We showcase specific examples of natural repeat proteins interacting with diverse ligands and also present examples of designed repeat protein–ligand interactions. PMID:18602006
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An alternate binding site for PPARγ ligands
Hughes, Travis S.; Giri, Pankaj Kumar; de Vera, Ian Mitchelle S.; Marciano, David P.; Kuruvilla, Dana S.; Shin, Youseung; Blayo, Anne-Laure; Kamenecka, Theodore M.; Burris, Thomas P.; Griffin, Patrick R.; Kojetin, Douglas J.
2014-01-01
PPARγ is a target for insulin sensitizing drugs such as glitazones, which improve plasma glucose maintenance in patients with diabetes. Synthetic ligands have been designed to mimic endogenous ligand binding to a canonical ligand-binding pocket to hyperactivate PPARγ. Here we reveal that synthetic PPARγ ligands also bind to an alternate site, leading to unique receptor conformational changes that impact coregulator binding, transactivation and target gene expression. Using structure-function studies we show that alternate site binding occurs at pharmacologically relevant ligand concentrations, and is neither blocked by covalently bound synthetic antagonists nor by endogenous ligands indicating non-overlapping binding with the canonical pocket. Alternate site binding likely contributes to PPARγ hyperactivation in vivo, perhaps explaining why PPARγ full and partial or weak agonists display similar adverse effects. These findings expand our understanding of PPARγ activation by ligands and suggest that allosteric modulators could be designed to fine tune PPARγ activity without competing with endogenous ligands. PMID:24705063
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A New Planning Template for Transit-Oriented Development
DOT National Transportation Integrated Search
2001-09-01
The Mineta Transportation Institute (MTI) at San Josi State University assigned a project team to design a planning template for transit-oriented development (TOD) that incorporates an understanding of nonwork travel, that is, trips for shopping, eat...
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Ma, Ming-Guo
2012-01-01
Hierarchically nanosized hydroxyapatite (HA) with flower-like structure assembled from nanosheets consisting of nanorod building blocks was successfully synthesized by using CaCl2, NaH2PO4, and potassium sodium tartrate via a hydrothermal method at 200°C for 24 hours. The effects of heating time and heating temperature on the products were investigated. As a chelating ligand and template molecule, the potassium sodium tartrate plays a key role in the formation of hierarchically nanostructured HA. On the basis of experimental results, a possible mechanism based on soft-template and self-assembly was proposed for the formation and growth of the hierarchically nanostructured HA. Cytotoxicity experiments indicated that the hierarchically nanostructured HA had good biocompatibility. It was shown by in-vitro experiments that mesenchymal stem cells could attach to the hierarchically nanostructured HA after being cultured for 48 hours. Objective The purpose of this study was to develop facile and effective methods for the synthesis of novel hydroxyapatite (HA) with hierarchical nanostructures assembled from independent and discrete nanobuilding blocks. Methods A simple hydrothermal approach was applied to synthesize HA by using CaCl2, NaH2PO4, and potassium sodium tartrate at 200°C for 24 hours. The cell cytotoxicity of the hierarchically nanostructured HA was tested by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Results HA displayed the flower-like structure assembled from nanosheets consisting of nanorod building blocks. The potassium sodium tartrate was used as a chelating ligand, inducing the formation and self-assembly of HA nanorods. The heating time and heating temperature influenced the aggregation and morphology of HA. The cell viability did not decrease with the increasing concentration of hierarchically nanostructured HA added. Conclusion A novel, simple and reliable hydrothermal route had been developed for the synthesis of hierarchically nanosized HA with flower-like structure assembled from nanosheets consisting of nanorod building blocks. The HA with the hierarchical nanostructure was formed via a soft-template assisted self-assembly mechanism. The hierarchically nanostructured HA has a good biocompatibility and essentially no in-vitro cytotoxicity. PMID:22619527
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Tong, Kuang; Zhang, Yuanzhi; Zhang, Sheng; Yu, Bin
2013-06-01
To provide an accurate method for osteotomy in the treatment of developmental dysplasia of the hip with steel osteotomy by three-dimensional reconstruction and Reverse Engineering technique. Between January 2011 and December 2012, 13 children with developmental dysplasia of the hip underwent steel osteotomy. 3D CT scan pelvic images were obtained and transferred via a DICOM network into a computer workstation to construct 3D models of the hip using Materialise Mimics 14.1 software in STL format. These models were imported into Imageware 12.0 software for steel osteotomy simulation until a stable hip was attained in the anatomical position for dislocation or subluxation of the hip in older children. The osteotomy navigational templates were designed according to the anatomical features after a stable hip was reconstructed. These navigational templates were manufactured using a rapid prototyping technique. The reconstruction hips in these children show good matching property and acetabulum cover. The computer-aided design of osteotomy template provides personalized and accurate solutions in the treatment of developmental dysplasia of the hip with steel osteotomy in older children.
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Wang, Huei-Tang; Taufany, Fadlilatul; Nachimuthu, Santhanamoorthi; Jiang, Jyh-Chiang
2014-05-01
The development of ruthenium dye-sensitizers with highly effective metal-to-ligand charge transfer (MLCT) characteristics and narrowed transition energy gaps are essential for the new generation of dye-sensitized solar cells. Here, we designed a novel anchoring ligand by inserting the cyanovinyl-branches inside the anchoring ligands of selected highly efficient dye-sensitizers and studied their intrinsic optical properties using theoretical methods. Our calculated results show that the designed ruthenium dyes provide good performances as sensitizers compared to the selected efficient dyes, because of their red-shift in the UV-visible absorption spectra with an increase in the absorption intensity, smaller energy gaps and thereby enhancing MLCT transitions. We found that, the designed anchoring ligand acts as an efficient "electron-acceptor" which boosts electron-transfer from a -NCS ligand to this ligand via a Ru-bridge, thus providing a way to lower the transition energy gap and enhance the MLCT transitions.
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Wu, Kevin; Doyle, Abigail G
2017-08-01
The field of Ni-catalysed cross-coupling has seen rapid recent growth because of the low cost of Ni, its earth abundance, and its ability to promote unique cross-coupling reactions. Whereas advances in the related field of Pd-catalysed cross-coupling have been driven by ligand design, the development of ligands specifically for Ni has received minimal attention. Here, we disclose a class of phosphines that enable the Ni-catalysed Csp 3 Suzuki coupling of acetals with boronic acids to generate benzylic ethers, a reaction that failed with known ligands for Ni and designer phosphines for Pd. Using parameters to quantify phosphine steric and electronic properties together with regression statistical analysis, we identify a model for ligand success. The study suggests that effective phosphines feature remote steric hindrance, a concept that could guide future ligand design tailored to Ni. Our analysis also reveals that two classic descriptors for ligand steric environment-cone angle and % buried volume-are not equivalent, despite their treatment in the literature.
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Wang, Yanzhao; Wang, Zhixun; Li, Yuxue; Wu, Gongde; Cao, Zheng; Zhang, Liming
2014-04-07
Most homogenous gold catalyses demand ≥ 0.5 mol% catalyst loading. Owing to the high cost of gold, these reactions are unlikely to be applicable in medium- or large-scale applications. Here we disclose a novel ligand design based on the privileged (1,1'-biphenyl)-2-ylphosphine framework that offers a potentially general approach to dramatically lowering catalyst loading. In this design, an amide group at the 3'-position of the ligand framework directs and promotes nucleophilic attack at the ligand gold complex-activated alkyne, which is unprecedented in homogenous gold catalysis considering the spatial challenge of using ligand to reach anti-approaching nucleophile in a linear P-Au-alkyne centroid structure. With such a ligand, the gold(I) complex becomes highly efficient in catalysing acid addition to alkynes, with a turnover number up to 99,000. Density functional theory calculations support the role of the amide moiety in directing the attack of carboxylic acid via hydrogen bonding.
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NASA Astrophysics Data System (ADS)
Wu, Kevin; Doyle, Abigail G.
2017-08-01
The field of Ni-catalysed cross-coupling has seen rapid recent growth because of the low cost of Ni, its earth abundance, and its ability to promote unique cross-coupling reactions. Whereas advances in the related field of Pd-catalysed cross-coupling have been driven by ligand design, the development of ligands specifically for Ni has received minimal attention. Here, we disclose a class of phosphines that enable the Ni-catalysed Csp3 Suzuki coupling of acetals with boronic acids to generate benzylic ethers, a reaction that failed with known ligands for Ni and designer phosphines for Pd. Using parameters to quantify phosphine steric and electronic properties together with regression statistical analysis, we identify a model for ligand success. The study suggests that effective phosphines feature remote steric hindrance, a concept that could guide future ligand design tailored to Ni. Our analysis also reveals that two classic descriptors for ligand steric environment—cone angle and % buried volume—are not equivalent, despite their treatment in the literature.
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Wang, Yanzhao; Wang, Zhixun; Li, Yuxue; Wu, Gongde; Cao, Zheng; Zhang, Liming
2014-01-01
Most homogenous gold catalyses demand ≥0.5 mol % catalyst loading. Due to the high cost of gold, these reactions are unlikely to be applicable in medium or large scale applications. Here we disclose a novel ligand design based on the privileged biphenyl-2-phosphine framework that offers a potentially general approach to dramatically lowering catalyst loading. In this design, an amide group at the 3’ position of the ligand framework directs and promotes nucleophilic attack at the ligand gold complex-activated alkyne, which is unprecedented in homogeneous gold catalysis considering the spatial challenge of using ligand to reach antiapproaching nucleophile in a linear P-Au-alkyne centroid structure. With such a ligand, the gold(I) complex becomes highly efficient in catalyzing acid addition to alkynes, with a turnover number up to 99,000. Density functional theory calculations support the role of the amide moiety in directing the attack of carboxylic acid via hydrogen bonding. PMID:24704803
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Huang, Ming-Wei; Liu, Shu-Ming; Zheng, Lei; Shi, Yan; Zhang, Jie; Li, Yan-Sheng; Yu, Guang-Yan; Zhang, Jian-Guo
2012-11-01
To enhance the accuracy of radioactive seed implants in the head and neck, a digital model individual template, containing information simultaneously on needle pathway and facial features, was designed to guide implantation with CT imaging. Thirty-one patients with recurrent and local advanced malignant tumors of head and neck after prior surgery and radiotherapy were involved in this study. Before (125)I implants, patients received CT scans based on 0.75mm thickness. And the brachytherapy treatment planning system (BTPS) software was used to make the implantation plan based on the CT images. Mimics software and Geomagic software were used to read the data containing CT images and implantation plan, and to design the individual template. Then the individual template containing the information of needle pathway and face features simultaneously was made through rapid prototyping (RP) technique. All patients received (125)I seeds interstitial implantation under the guide of the individual template and CT. The individual templates were positioned easily and accurately, and were stable. After implants, treatment quality evaluation was made by CT and TPS. The seeds and dosages distribution (D(90),V(100),V(150)) were well meet the treatment requirement. Clinical practice confirms that this approach can facilitate easier and more accurate implantation.
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ERIC Educational Resources Information Center
Dobozy, Eva
2012-01-01
In this paper, the five interlocking de Bono LAMS sequences are introduced as a new form of generic template designs. This transdisciplinary knowledge-mobilising strategy is based on Edward de Bono's attention-directing ideas and thinking skills, commonly known as the CoRT tools. The development of the de Bono LAMS sequence series is an important…
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Bridge, Heather; Smolskis, Mary; Bianchine, Peter; Dixon, Dennis O.; Kelly, Grace; Herpin, Betsey; Tavel, Jorge
2009-01-01
Background: A clinical research protocol document must reflect both sound scientific rationale as well as local, national and, when applicable, international regulatory and human subject protections requirements. These requirements originate from a variety of sources, undergo frequent revision and are subject to interpretation. Tools to assist clinical investigators in the production of clinical protocols could facilitate navigating these requirements and ultimately increase the efficiency of clinical research. Purpose: The National Institute of Allergy and Infectious Diseases (NIAID) developed templates for investigators to serve as the foundation for protocol development. These protocol templates are designed as tools to support investigators in developing clinical protocols. Methods: NIAID established a series of working groups to determine how to improve its capacity to conduct clinical research more efficiently and effectively. The Protocol Template Working Group was convened to determine what protocol templates currently existed within NIAID and whether standard NIAID protocol templates should be produced. After review and assessment of existing protocol documents and requirements, the group reached consensus about required and optional content, determined the format and identified methods for distribution as well as education of investigators in the use of these templates. Results: The templates were approved by the NIAID Executive Committee in 2006 and posted as part of the NIAID Clinical Research Toolkit[1]website for broad access. These documents require scheduled revisions to stay current with regulatory and policy changes. Limitations: The structure of any clinical protocol template, whether comprehensive or specific to a particular study phase, setting or design, affects how it is used by investigators. Each structure presents its own set of advantages and disadvantages. While useful, protocol templates are not stand-alone tools for creating an optimal protocol document but must be complemented by institutional resources and support. Education and guidance of investigators in the appropriate use of templates is necessary to ensure a complete yet concise protocol document. Due to changing regulatory requirements, clinical protocol templates cannot become static but require frequent revisions. Conclusions: Standard protocol templates that meet applicable regulations can be important tools to assist investigators in the effective conduct of clinical research, but they require dedicated resources and ongoing input from key stakeholders. PMID:19625326
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Kerber, Kevin A; Hofer, Timothy P; Meurer, William J; Fendrick, A Mark; Morgenstern, Lewis B
2011-03-24
Clinical documentation systems, such as templates, have been associated with process utilization. The T-System emergency department (ED) templates are widely used but lacking are analyses of the templates association with processes. This system is also unique because of the many different template options available, and thus the selection of the template may also be important. We aimed to describe the selection of templates in ED dizziness presentations and to investigate the association between items on templates and process utilization. Dizziness visits were captured from a population-based study of EDs that use documentation templates. Two relevant process outcomes were assessed: head computerized tomography (CT) scan and nystagmus examination. Multivariable logistic regression was used to estimate the probability of each outcome for patients who did or did not receive a relevant-item template. Propensity scores were also used to adjust for selection effects. The final cohort was 1,485 visits. Thirty-one different templates were used. Use of a template with a head CT item was associated with an increase in the adjusted probability of head CT utilization from 12.2% (95% CI, 8.9%-16.6%) to 29.3% (95% CI, 26.0%-32.9%). The adjusted probability of documentation of a nystagmus assessment increased from 12.0% (95%CI, 8.8%-16.2%) when a nystagmus-item template was not used to 95.0% (95% CI, 92.8%-96.6%) when a nystagmus-item template was used. The associations remained significant after propensity score adjustments. Providers use many different templates in dizziness presentations. Important differences exist in the various templates and the template that is used likely impacts process utilization, even though selection may be arbitrary. The optimal design and selection of templates may offer a feasible and effective opportunity to improve care delivery.
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Ligand design for riboswitches, an emerging target class for novel antibiotics.
Rekand, Illimar Hugo; Brenk, Ruth
2017-09-01
Riboswitches are cis-acting gene regulatory elements and constitute potential targets for new antibiotics. Recent studies in this field have started to explore these targets for drug discovery. New ligands found by fragment screening, design of analogs of the natural ligands or serendipitously by phenotypic screening have shown antibacterial effects in cell assays against a range of bacteria strains and in animal models. In this review, we highlight the most advanced drug design work of riboswitch ligands and discuss the challenges in the field with respect to the development of antibiotics with a new mechanism of action.
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Cornelius, Carl-Peter; Giessler, Goetz Andreas; Wilde, Frank; Metzger, Marc Christian; Mast, Gerson; Probst, Florian Andreas
2016-03-01
Computer-assisted planning and intraoperative implementation using templates have become appreciated modalities in craniofacial reconstruction with fibula and DCIA flaps due to saving in operation time, improved accuracy of osteotomies and easy insetting. Up to now, a similar development for flaps from the subscapular vascular system, namely the lateral scapular border and tip, has not been addressed in the literature. A cohort of 12 patients who underwent mandibular (n = 10) or maxillary (n = 2) reconstruction with free flaps containing the lateral scapular border and tip using computer-assisted planning, stereolithography (STL) models and selective laser sintered (SLS) templates for bone contouring and sub-segmentation osteotomies was reviewed focussing on iterations in the design of computer generated tools and templates. The technical evolution migrated from hybrid STL models over SLS templates for cut out as well as sub-segmentation with a uniplanar framework to plug-on tandem template assemblies providing a biplanar access for the in toto cut out from the posterior aspect in succession with contouring into sub-segments from the medial side. The latest design version is the proof of concept that virtual planning of bone flaps from the lateral scapular border can be successfully transferred into surgery by appropriate templates. Copyright © 2015 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
McCann, Billy W.; Silva, Nuwan De; Windus, Theresa L.
Computer-aided molecular design and high-throughput screening of viable host architectures can significantly reduce the efforts in the design of novel ligands for efficient extraction of rare earth elements. This paper presents a computational approach to the deliberate design of bis-phosphine oxide host architectures that are structurally organized for complexation of trivalent lanthanides. Molecule building software, HostDesigner, was interfaced with molecular mechanics software, PCModel, providing a tool for generating and screening millions of potential R 2(O)P-link-P(O)R 2 ligand geometries. The molecular mechanics ranking of ligand structures is consistent with both the solution-phase free energies of complexation obtained with density functional theorymore » and the performance of known bis-phosphine oxide extractants. For the case where link is -CH 2-, evaluation of the ligand geometry provides the first characterization of a steric origin for the ‘anomalous aryl strengthening’ effect. The design approach has identified a number of novel bis-phosphine oxide ligands that are better organized for lanthanide complexation than previously studied examples.« less
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Akparov, Valery; Timofeev, Vladimir; Khaliullin, Ilyas; Švedas, Vytas; Kuranova, Inna
2018-03-01
Carboxypeptidase B (EC 3.4.17.2) (CPB) is commonly used in the industrial insulin production and as a template for drug design. However, its ability to discriminate substrates with hydrophobic, hydrophilic, and charged side chains is not well understood. We report structure of CPB complex with a transition state analog N-sulfamoyl-L-phenylalanine solved at 1.74Å. The study provided an insight into structural basis of CPB substrate specificity. Ligand binding is affected by structure-depended conformational changes of Asp255 in S1'-subsite, interactions with Asn144 and Arg145 in C-terminal binding subsite, and Glu270 in the catalytic center. Side chain of the non-specific substrate analog SPhe in comparison with that of specific substrate analog SArg (reported earlier) not only loses favorable electrostatic interactions and two hydrogen bonds with Asp255 and three fixed water molecules, but is forced to be in the unfavorable hydrophilic environment. Thus, Ser207, Gly253, Tyr248, and Asp255 residues play major role in the substrate recognition by S1'-subsite.
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Docking and Virtual Screening Strategies for GPCR Drug Discovery.
Beuming, Thijs; Lenselink, Bart; Pala, Daniele; McRobb, Fiona; Repasky, Matt; Sherman, Woody
2015-01-01
Progress in structure determination of G protein-coupled receptors (GPCRs) has made it possible to apply structure-based drug design (SBDD) methods to this pharmaceutically important target class. The quality of GPCR structures available for SBDD projects fall on a spectrum ranging from high resolution crystal structures (<2 Å), where all water molecules in the binding pocket are resolved, to lower resolution (>3 Å) where some protein residues are not resolved, and finally to homology models that are built using distantly related templates. Each GPCR project involves a distinct set of opportunities and challenges, and requires different approaches to model the interaction between the receptor and the ligands. In this review we will discuss docking and virtual screening to GPCRs, and highlight several refinement and post-processing steps that can be used to improve the accuracy of these calculations. Several examples are discussed that illustrate specific steps that can be taken to improve upon the docking and virtual screening accuracy. While GPCRs are a unique target class, many of the methods and strategies outlined in this review are general and therefore applicable to other protein families.
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Computational design of environmental sensors for the potent opioid fentanyl
Bick, Matthew J.; Greisen, Per J.; Morey, Kevin J.; ...
2017-09-19
Here, we describe the computational design of proteins that bind the potent analgesic fentanyl. Our approach employs a fast docking algorithm to find shape complementary ligand placement in protein scaffolds, followed by design of the surrounding residues to optimize binding affinity. Co-crystal structures of the highest affinity binder reveal a highly preorganized binding site, and an overall architecture and ligand placement in close agreement with the design model. We also use the designs to generate plant sensors for fentanyl by coupling ligand binding to design stability. The method should be generally useful for detecting toxic hydrophobic compounds in the environment.
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Computational design of environmental sensors for the potent opioid fentanyl
Morey, Kevin J; Antunes, Mauricio S; La, David; Sankaran, Banumathi; Reymond, Luc; Johnsson, Kai; Medford, June I
2017-01-01
We describe the computational design of proteins that bind the potent analgesic fentanyl. Our approach employs a fast docking algorithm to find shape complementary ligand placement in protein scaffolds, followed by design of the surrounding residues to optimize binding affinity. Co-crystal structures of the highest affinity binder reveal a highly preorganized binding site, and an overall architecture and ligand placement in close agreement with the design model. We use the designs to generate plant sensors for fentanyl by coupling ligand binding to design stability. The method should be generally useful for detecting toxic hydrophobic compounds in the environment. PMID:28925919
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Computational design of environmental sensors for the potent opioid fentanyl
DOE Office of Scientific and Technical Information (OSTI.GOV)
Bick, Matthew J.; Greisen, Per J.; Morey, Kevin J.
Here, we describe the computational design of proteins that bind the potent analgesic fentanyl. Our approach employs a fast docking algorithm to find shape complementary ligand placement in protein scaffolds, followed by design of the surrounding residues to optimize binding affinity. Co-crystal structures of the highest affinity binder reveal a highly preorganized binding site, and an overall architecture and ligand placement in close agreement with the design model. We also use the designs to generate plant sensors for fentanyl by coupling ligand binding to design stability. The method should be generally useful for detecting toxic hydrophobic compounds in the environment.
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Discriminative structural approaches for enzyme active-site prediction.
Kato, Tsuyoshi; Nagano, Nozomi
2011-02-15
Predicting enzyme active-sites in proteins is an important issue not only for protein sciences but also for a variety of practical applications such as drug design. Because enzyme reaction mechanisms are based on the local structures of enzyme active-sites, various template-based methods that compare local structures in proteins have been developed to date. In comparing such local sites, a simple measurement, RMSD, has been used so far. This paper introduces new machine learning algorithms that refine the similarity/deviation for comparison of local structures. The similarity/deviation is applied to two types of applications, single template analysis and multiple template analysis. In the single template analysis, a single template is used as a query to search proteins for active sites, whereas a protein structure is examined as a query to discover the possible active-sites using a set of templates in the multiple template analysis. This paper experimentally illustrates that the machine learning algorithms effectively improve the similarity/deviation measurements for both the analyses.
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Silver nanowires-templated metal oxide for broadband Schottky photodetector
DOE Office of Scientific and Technical Information (OSTI.GOV)
Patel, Malkeshkumar; Kim, Hong-Sik; Kim, Joondong, E-mail: joonkim@inu.ac.kr
2016-04-04
Silver nanowires (AgNWs)-templated transparent metal oxide layer was applied for Si Schottky junction device, which remarked the record fastest photoresponse of 3.4 μs. Self-operating AgNWs-templated Schottky photodetector showed broad wavelength photodetection with high responsivity (42.4 A W{sup −1}) and detectivity (2.75 × 10{sup 15} Jones). AgNWs-templated indium-tin-oxide (ITO) showed band-to-band excitation due to the internal photoemission, resulting in significant carrier collection performances. Functional metal oxide layer was formed by AgNWs-templated from ITO structure. The grown ITO above AgNWs has a cylindrical shape and acts as a thermal protector of AgNWs for high temperature environment without any deformation. We developed thermal stable AgNWs-templated transparent oxidemore » devices and demonstrated the working mechanism of AgNWs-templated Schottky devices. We may propose the high potential of hybrid transparent layer design for various photoelectric applications, including solar cells.« less
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Computer-Aided Molecular Design of Bis-phosphine Oxide Lanthanide Extractants
McCann, Billy W.; Silva, Nuwan De; Windus, Theresa L.; ...
2016-02-17
Computer-aided molecular design and high-throughput screening of viable host architectures can significantly reduce the efforts in the design of novel ligands for efficient extraction of rare earth elements. This paper presents a computational approach to the deliberate design of bis-phosphine oxide host architectures that are structurally organized for complexation of trivalent lanthanides. Molecule building software, HostDesigner, was interfaced with molecular mechanics software, PCModel, providing a tool for generating and screening millions of potential R 2(O)P-link-P(O)R 2 ligand geometries. The molecular mechanics ranking of ligand structures is consistent with both the solution-phase free energies of complexation obtained with density functional theorymore » and the performance of known bis-phosphine oxide extractants. For the case where link is -CH 2-, evaluation of the ligand geometry provides the first characterization of a steric origin for the ‘anomalous aryl strengthening’ effect. The design approach has identified a number of novel bis-phosphine oxide ligands that are better organized for lanthanide complexation than previously studied examples.« less
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Lowekamp, Bradley C.; Chen, David T.; Ibáñez, Luis; Blezek, Daniel
2013-01-01
SimpleITK is a new interface to the Insight Segmentation and Registration Toolkit (ITK) designed to facilitate rapid prototyping, education and scientific activities via high level programming languages. ITK is a templated C++ library of image processing algorithms and frameworks for biomedical and other applications, and it was designed to be generic, flexible and extensible. Initially, ITK provided a direct wrapping interface to languages such as Python and Tcl through the WrapITK system. Unlike WrapITK, which exposed ITK's complex templated interface, SimpleITK was designed to provide an easy to use and simplified interface to ITK's algorithms. It includes procedural methods, hides ITK's demand driven pipeline, and provides a template-less layer. Also SimpleITK provides practical conveniences such as binary distribution packages and overloaded operators. Our user-friendly design goals dictated a departure from the direct interface wrapping approach of WrapITK, toward a new facade class structure that only exposes the required functionality, hiding ITK's extensive template use. Internally SimpleITK utilizes a manual description of each filter with code-generation and advanced C++ meta-programming to provide the higher-level interface, bringing the capabilities of ITK to a wider audience. SimpleITK is licensed as open source software library under the Apache License Version 2.0 and more information about downloading it can be found at http://www.simpleitk.org. PMID:24416015
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GALAHAD: 1. Pharmacophore identification by hypermolecular alignment of ligands in 3D
NASA Astrophysics Data System (ADS)
Richmond, Nicola J.; Abrams, Charlene A.; Wolohan, Philippa R. N.; Abrahamian, Edmond; Willett, Peter; Clark, Robert D.
2006-09-01
Alignment of multiple ligands based on shared pharmacophoric and pharmacosteric features is a long-recognized challenge in drug discovery and development. This is particularly true when the spatial overlap between structures is incomplete, in which case no good template molecule is likely to exist. Pair-wise rigid ligand alignment based on linear assignment (the LAMDA algorithm) has the potential to address this problem (Richmond et al. in J Mol Graph Model 23:199-209, 2004). Here we present the version of LAMDA embodied in the GALAHAD program, which carries out multi-way alignments by iterative construction of hypermolecules that retain the aggregate as well as the individual attributes of the ligands. We have also generalized the cost function from being purely atom-based to being one that operates on ionic, hydrogen bonding, hydrophobic and steric features. Finally, we have added the ability to generate useful partial-match 3D search queries from the hypermolecules obtained. By running frozen conformations through the GALAHAD program, one can utilize the extended version of LAMDA to generate pharmacophores and pharmacosteres that agree well with crystal structure alignments for a range of literature datasets, with minor adjustments of the default parameters generating even better models. Allowing for inclusion of partial match constraints in the queries yields pharmacophores that are consistently a superset of full-match pharmacophores identified in previous analyses, with the additional features representing points of potentially beneficial interaction with the target.
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Conformation-induced remote meta-C-H activation of amines
NASA Astrophysics Data System (ADS)
Tang, Ri-Yuan; Li, Gang; Yu, Jin-Quan
2014-03-01
Achieving site selectivity in carbon-hydrogen (C-H) functionalization reactions is a long-standing challenge in organic chemistry. The small differences in intrinsic reactivity of C-H bonds in any given organic molecule can lead to the activation of undesired C-H bonds by a non-selective catalyst. One solution to this problem is to distinguish C-H bonds on the basis of their location in the molecule relative to a specific functional group. In this context, the activation of C-H bonds five or six bonds away from a functional group by cyclometallation has been extensively studied. However, the directed activation of C-H bonds that are distal to (more than six bonds away) functional groups has remained challenging, especially when the target C-H bond is geometrically inaccessible to directed metallation owing to the ring strain encountered in cyclometallation. Here we report a recyclable template that directs the olefination and acetoxylation of distal meta-C-H bonds--as far as 11 bonds away--of anilines and benzylic amines. This template is able to direct the meta-selective C-H functionalization of bicyclic heterocycles via a highly strained, tricyclic-cyclophane-like palladated intermediate. X-ray and nuclear magnetic resonance studies reveal that the conformational biases induced by a single fluorine substitution in the template can be enhanced by using a ligand to switch from ortho- to meta-selectivity.
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Conformation-induced remote meta-C-H activation of amines.
Tang, Ri-Yuan; Li, Gang; Yu, Jin-Quan
2014-03-13
Achieving site selectivity in carbon-hydrogen (C-H) functionalization reactions is a long-standing challenge in organic chemistry. The small differences in intrinsic reactivity of C-H bonds in any given organic molecule can lead to the activation of undesired C-H bonds by a non-selective catalyst. One solution to this problem is to distinguish C-H bonds on the basis of their location in the molecule relative to a specific functional group. In this context, the activation of C-H bonds five or six bonds away from a functional group by cyclometallation has been extensively studied. However, the directed activation of C-H bonds that are distal to (more than six bonds away) functional groups has remained challenging, especially when the target C-H bond is geometrically inaccessible to directed metallation owing to the ring strain encountered in cyclometallation. Here we report a recyclable template that directs the olefination and acetoxylation of distal meta-C-H bonds--as far as 11 bonds away--of anilines and benzylic amines. This template is able to direct the meta-selective C-H functionalization of bicyclic heterocycles via a highly strained, tricyclic-cyclophane-like palladated intermediate. X-ray and nuclear magnetic resonance studies reveal that the conformational biases induced by a single fluorine substitution in the template can be enhanced by using a ligand to switch from ortho- to meta-selectivity.
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Quantum dot nanocrystals having guanosine imprinted nanoshell for DNA recognition.
Diltemiz, Sibel Emir; Say, Ridvan; Büyüktiryaki, Sibel; Hür, Deniz; Denizli, Adil; Ersöz, Arzu
2008-05-30
Molecular imprinted polymers (MIPs) as a recognition element for sensors are increasingly of interest and MIP nanoparticles have started to appear in the literature. In this study, we have proposed a novel thiol ligand-capping method with polymerizable methacryloylamido-cysteine (MAC) attached to CdS quantum dots (QDs), reminiscent of a self-assembled monolayer and have reconstructed surface shell by synthetic host polymers based on molecular imprinting method for DNA recognition. In this method, methacryloylamidohistidine-platinium (MAH-Pt(II)) is used as a new metal-chelating monomer via metal coordination-chelation interactions and guanosine templates of DNA. Nanoshell sensors with guanosine templates give a cavity that is selective for guanosine and its analogues. The guanosine can simultaneously chelate to Pt(II) metal ion and fit into the shape-selective cavity. Thus, the interaction between Pt(II) ion and free coordination spheres has an effect on the binding ability of the CdS QD nanosensor. The binding affinity of the guanosine imprinted nanocrystals has investigated by using the Langmuir and Scatchard methods, and experiments have shown the shape-selective cavity formation with O6 and N7 of a guanosine nucleotide (K(a) = 4.841x10(6) mol L(-1)) and a free guanine base (K(a) = 0.894x10(6) mol L(-1)). Additionally, the guanosine template of the nanocrystals is more favored for single stranded DNA compared to double stranded DNA.
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NASA Astrophysics Data System (ADS)
Lermusiaux, Laurent; Bidault, Sebastien
2016-03-01
The nanometer-scale sensitivity of plasmon coupling allows the translation of minute morphological changes in nanostructures into macroscopic optical signals. In particular, single nanostructure scattering spectroscopy provides a direct estimation of interparticle distances in gold nanoparticle (AuNP) dimers linked by a short DNA double-strand [M. P. Busson et al, Nano Lett. 11, 5060 (2011)]. We demonstrate here that this spectroscopic information can be inferred from simple widefield measurements on a calibrated color camera [L. Lermusiaux et al, ACS Nano 9, 978 (2015)]. This allows us to analyze the influence of electrostatic and steric interparticle interactions on the morphology of DNA-templated AuNP groupings. Furthermore, polarization-resolved measurements on a color CCD provide a parallel imaging of AuNP dimer orientations. We apply this spectroscopic characterization to identify dimers featuring two different conformations of the same DNA template. In practice, the biomolecular scaffold contains a hairpin-loop that opens after hybridization to a specific DNA sequence and increases the interparticle distance [L. Lermusiaux et al, ACS Nano 6, 10992 (2012)]. These results open exciting perspectives for the parallel sensing of single specific DNA strands using plasmon rulers. We discuss the limits of this approach in terms of the physicochemical stability and reactivity of these nanostructures and demonstrate the importance of engineering the AuNP surface chemistry, in particular using amphiphilic ligands [L. Lermusiaux and S. Bidault, Small (2015), in press].
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Moroni, Elisabetta; Zhao, Huiping; Blagg, Brian S.J.; Colombo, Giorgio
2014-01-01
The interaction that occurs between molecules is a dynamic process that impacts both structural and conformational properties of the ligand and the ligand binding site. Herein, we investigate the dynamic cross-talk between a protein and the ligand as a source for new opportunities in ligand design. Analysis of the formation/disappearance of protein pockets produced in response to a first-generation inhibitor assisted in the identification of functional groups that could be introduced onto scaffolds to facilitate optimal binding, which allowed for increased binding with previously uncharacterized regions. MD simulations were used to elucidate primary changes that occur in the Hsp90 C-terminal binding pocket in the presence of first-generation ligands. This data was then used to design ligands that adapt to these receptor conformations, which provides access to an energy landscape that is not visible in a static model. The newly synthesized compounds demonstrated anti-proliferative activity at ~150 nanomolar concentration. The method identified herein may be used to design chemical probes that provide additional information on structural variations of Hsp90 C-terminal binding site. PMID:24397468
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Structural Analysis of Chemokine Receptor–Ligand Interactions
2017-01-01
This review focuses on the construction and application of structural chemokine receptor models for the elucidation of molecular determinants of chemokine receptor modulation and the structure-based discovery and design of chemokine receptor ligands. A comparative analysis of ligand binding pockets in chemokine receptors is presented, including a detailed description of the CXCR4, CCR2, CCR5, CCR9, and US28 X-ray structures, and their implication for modeling molecular interactions of chemokine receptors with small-molecule ligands, peptide ligands, and large antibodies and chemokines. These studies demonstrate how the integration of new structural information on chemokine receptors with extensive structure–activity relationship and site-directed mutagenesis data facilitates the prediction of the structure of chemokine receptor–ligand complexes that have not been crystallized. Finally, a review of structure-based ligand discovery and design studies based on chemokine receptor crystal structures and homology models illustrates the possibilities and challenges to find novel ligands for chemokine receptors. PMID:28165741
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Ollikainen, Noah; de Jong, René M; Kortemme, Tanja
2015-01-01
Interactions between small molecules and proteins play critical roles in regulating and facilitating diverse biological functions, yet our ability to accurately re-engineer the specificity of these interactions using computational approaches has been limited. One main difficulty, in addition to inaccuracies in energy functions, is the exquisite sensitivity of protein-ligand interactions to subtle conformational changes, coupled with the computational problem of sampling the large conformational search space of degrees of freedom of ligands, amino acid side chains, and the protein backbone. Here, we describe two benchmarks for evaluating the accuracy of computational approaches for re-engineering protein-ligand interactions: (i) prediction of enzyme specificity altering mutations and (ii) prediction of sequence tolerance in ligand binding sites. After finding that current state-of-the-art "fixed backbone" design methods perform poorly on these tests, we develop a new "coupled moves" design method in the program Rosetta that couples changes to protein sequence with alterations in both protein side-chain and protein backbone conformations, and allows for changes in ligand rigid-body and torsion degrees of freedom. We show significantly increased accuracy in both predicting ligand specificity altering mutations and binding site sequences. These methodological improvements should be useful for many applications of protein-ligand design. The approach also provides insights into the role of subtle conformational adjustments that enable functional changes not only in engineering applications but also in natural protein evolution.
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Jiang, Lianghai; Dong, Liang; Tan, Mingsheng; Qi, Yingna; Yang, Feng; Yi, Ping; Tang, Xiangsheng
2017-01-01
Background Atlantoaxial posterior pedicle screw fixation has been widely used for treatment of atlantoaxial instability (AAI). However, precise and safe insertion of atlantoaxial pedicle screws remains challenging. This study presents a modified drill guide template based on a previous template for atlantoaxial pedicle screw placement. Material/Methods Our study included 54 patients (34 males and 20 females) with AAI. All the patients underwent posterior atlantoaxial pedicle screw fixation: 25 patients underwent surgery with the use of a modified drill guide template (template group) and 29 patients underwent surgery via the conventional method (conventional group). In the template group, a modified drill guide template was designed for each patient. The modified drill guide template and intraoperative fluoroscopy were used for surgery in the template group, while only intraoperative fluoroscopy was used in the conventional group. Results Of the 54 patients, 52 (96.3%) completed the follow-up for more than 12 months. The template group had significantly lower intraoperative fluoroscopy frequency (p<0.001) and higher accuracy of screw insertion (p=0.045) than the conventional group. There were no significant differences in surgical duration, intraoperative blood loss, or improvement of neurological function between the 2 groups (p>0.05). Conclusions Based on the results of this study, it is feasible to use the modified drill guide template for atlantoaxial pedicle screw placement. Using the template can significantly lower the screw malposition rate and the frequency of intraoperative fluoroscopy. PMID:28301445
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Effect of digital template in the assistant of a giant condylar osteochondroma resection.
Bai, Guo; He, Dongmei; Yang, Chi; Lu, Chuan; Huang, Dong; Chen, Minjie; Yuan, Jianbing
2014-05-01
Exostosis osteochondroma is usually resected with the whole condyle even part of it is not involved. This study was to report the effect of using digital template in the assistant of resection while protecting the uninvolved condyle. We used computer-aided design technique in the assistant of making preoperative plan of a patient with giant condylar osteochondroma of exogenous type, including determining the boundary between the tumor and the articular surface of condyle, and designing the virtual tumor resection plane, surgical approach, and remove-out path of the tumor. The digital osteotomy template was made by rapid prototyping technique based on the preoperative plan. Postoperative CT scan was performed and merged with the preoperative CT by the Proplan 1.3 system to evaluate the accuracy of surgical resection with the guide of digital template. The osteotomy template was attached to the lateral surface of condyle accurately, and the tumor was removed totally by the guide of the template without injuries to adjacent nerves and vessels. Postoperative CT showed that the osteochondroma was removed completely and the unaffected articular surface of condyle was preserved well. The merging of postoperative and preoperative CT by Proplan 1.3 system showed the outcome of the operation matched with the preoperative planning quite well with an error of 0.92 mm. There was no sign of recurrence after 6 months of follow-up. The application of digital template could improve the accuracy of the giant condylar tumor resection and help to preserve the uninvolved condyle. The use of digital template could reduce injuries to the nerves and vessels as well as save time for the operation.
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Cueva, J.P.; Chemel, B.R.; Juncosa, J.I.; Lill, M.A.; Watts, V.J.; Nichols, D.E.
2012-01-01
Efforts to develop selective agonists for dopamine D 1-like receptors led to the discovery of dihydrexidine and doxanthrine, two bioisosteric ??-phenyldopamine-type full agonist ligands that display selectivity and potency at D 1-like receptors. We report herein an improved methodology for the synthesis of substituted chromanoisoquinolines (doxanthrine derivatives) and the evaluation of several new compounds for their ability to bind to D 1- and D 2-like receptors. Identical pendant phenyl ring substitutions on the dihydrexidine and doxanthrine templates surprisingly led to different effects on D 1-like receptor binding, suggesting important differences between the interactions of these ligands with the D 1 receptor. We propose, based on the biological results and molecular modeling studies, that slight conformational differences between the tetralin and chroman-based compounds lead to a shift in the location of the pendant ring substituents within the receptor. ?? 2011 Elsevier Ltd. All rights reserved.
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2-Acylpyrroles as mono-anionic O,N-chelating ligands in silicon coordination chemistry.
Kämpfe, Alexander; Brendler, Erica; Kroke, Edwin; Wagler, Jörg
2014-07-21
Kryptopyrrole (2,4-dimethyl-3-ethylpyrrole) was acylated with, for example, benzoyl chloride to afford 2-benzoyl-3,5-dimethyl-4-ethylpyrrole (L(1)H). With SiCl4 this ligand reacts under liberation of HCl and formation of the complex L(1)2SiCl2. In related reactions with HSiCl3 or H2SiCl2, the same chlorosilicon complex is formed under liberation of HCl and H2 or liberation of H2, respectively. The chlorine atoms of L(1)2SiCl2 can be replaced by fluoride and triflate using ZnF2 and Me3Si-OTf, respectively. The use of a supporting base (triethylamine) is required for the complexation of phenyltrichlorosilane and diphenyldichlorosilane. The complexes L(1)2SiCl2, L(1)2SiF2, L(1)2Si(OTf)2, L(1)2SiPhCl, and L(1)2SiPh2 exhibit various configurations of the octahedral silicon coordination spheres (i.e. cis or trans configuration of the monodentate substituents, different orientations of the bidentate chelating ligands relative to each other). Furthermore, cationic silicon complexes L(1)3Si(+) and L(1) SiPh(+) were synthesized by chloride abstraction with GaCl3. In contrast, reaction of L(1)2SiCl2 with a third equivalent of L(1)H in the presence of excess triethylamine produced a charge-neutral hexacoordinate Si complex with a new tetradentate chelating ligand which formed by Si-templated C-C coupling of two ligands L(1). © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Field Encapsulation Library The FEL 2.2 User Guide
NASA Technical Reports Server (NTRS)
Moran, Patrick J.; Henze, Chris; Ellsworth, David
1999-01-01
This document describes version 2.2 of the Field Encapsulation Library (FEL), a library of mesh and field classes. FEL is a library for programmers - it is a "building block" enabling the rapid development of applications by a user. Since FEL is a library intended for code development, it is essential that enough technical detail be provided so that one can make full use of the code. Providing such detail requires some assumptions with respect to the reader's familiarity with the library implementation language, C++, particularly C++ with templates. We have done our best to make the explanations accessible to those who may not be completely C++ literate. Nevertheless, familiarity with the language will certainly help one's understanding of how and why things work the way they do. One consolation is that the level of understanding essential for using the library is significantly less than the level that one should have in order to modify or extend the library. One more remark on C++ templates: Templates have been a source of both joy and frustration for us. The frustration stems from the lack of mature or complete implementations that one has to work with. Template problems rear their ugly head particularly when porting. When porting C code, successfully compiling to a set of object files typically means that one is almost done. With templated C++ and the current state of the compilers and linkers, generating the object files is often only the beginning of the fun. On the other hand, templates are quite powerful. Used judiciously, templates enable more succinct designs and more efficient code. Templates also help with code maintenance. Designers can avoid creating objects that are the same in many respects, but not exactly the same. For example, FEL fields are templated by node type, thus the code for scalar fields and vector fields is shared. Furthermore, node type templating allows the library user to instantiate fields with data types not provided by the FEL authors. This type of flexibility would be difficult to offer without the support of the language. For users who may be having template-related problems, we offer the consolation that support for C++ templates is destined to improve with time. Efforts such as the Standard Template Library (STL) will inevitably drive vendors to provide more thorough, optimized tools for template code development. Furthermore, the benefits will become harder to resist for those who currently subscribe to the least-common-denominator "code it all in C" strategy. May FEL bring you both increased productivity and aesthetic satisfaction.
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Monosaccharides as Scaffolds for the Synthesis of Novel Compounds
NASA Astrophysics Data System (ADS)
Murphy, Paul V.; Velasco-Torrijos, Trinidad
This chapter focuses on monosaccharides and scaffolds their derivatives as scaffolds for the synthesis of primarily bioactive compounds. Such carbohydrate derivatives have been designed to modulate mainly protein-protein and peptide-protein interactions although modulators of carbohydrate-protein and carbohydrate-nucleic acid interactions have also been of interest. The multiple hydroxyl groups that are present on saccharides have made pyranose, furanose and iminosugars ideal templates or scaffolds to which recognition or pharmacophoric groups can be grafted to generate novel compounds for medicinal chemistry. The synthesis of compounds for evaluations require strategies for regioselective reactions of saccharide hydroxyl groups and use of orthogonally stable protecting groups. Syntheses have been carried out on the solid phase and in solution. Also the use of uronic acids, amino sugars and sugar amino acids has facilitated the synthesis of peptidomimetics and prospecting libraries as they enable, through presence of amino or carboxylic acid groups, chemoselective approaches to be employed in solution and on solid phase. Sugar amino acids are readily incorporated, as peptide isosteres, to generate sugar-peptide hybrids or for the synthesis of novel carbopeptoids . The synthesis of new cyclic compounds, derived in part from saccharides, and their application as scaffolds is an emerging area and recent examples include spirocyclic compounds, benzodiazepine-saccharide hybrids and macrolide-saccharide hybrids. Potent bioactive saccharide derivatives have been identified that include enzyme inhibitors , somatostatin receptor ligands, integrin ligands, anti-viral compounds, shiga toxin inhibitors and cell growth inhibitors. Some saccharide derivatives have demonstrated improved cellular permeability when compared with peptides and are in clinical trials.
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Pradeepkiran, Jangampalli Adi; Kumar, Konidala Kranthi; Kumar, Yellapu Nanda; Bhaskar, Matcha
2015-01-01
The zoonotic disease brucellosis, a chronic condition in humans affecting renal and cardiac systems and causing osteoarthritis, is caused by Brucella, a genus of Gram-negative, facultative, intracellular pathogens. The mode of transmission and the virulence of the pathogens are still enigmatic. Transcription regulatory elements, such as rho proteins, play an important role in the termination of transcription and/or the selection of genes in Brucella. Adverse effects of the transcription inhibitors play a key role in the non-successive transcription challenges faced by the pathogens. In the investigation presented here, we computationally predicted the transcription termination factor rho (TtFRho) inhibitors against Brucella melitensis 16M via a structure-based method. In view the unknown nature of its crystal structure, we constructed a robust three-dimensional homology model of TtFRho’s structure by comparative modeling with the crystal structure of the Escherichia coli TtFRho (Protein Data Bank ID: 1PVO) as a template in MODELLER (v 9.10). The modeled structure was optimized by applying a molecular dynamics simulation for 2 ns with the CHARMM (Chemistry at HARvard Macromolecular Mechanics) 27 force field in NAMD (NAnoscale Molecular Dynamics program; v 2.9) and then evaluated by calculating the stereochemical quality of the protein. The flexible docking for the interaction phenomenon of the template consists of ligand-related inhibitor molecules from the ZINC (ZINC Is Not Commercial) database using a structure-based virtual screening strategy against minimized TtFRho. Docking simulations revealed two inhibitors compounds – ZINC24934545 and ZINC72319544 – that showed high binding affinity among 2,829 drug analogs that bind with key active-site residues; these residues are considered for protein-ligand binding and unbinding pathways via steered molecular dynamics simulations. Arg215 in the model plays an important role in the stability of the protein-ligand complex via a hydrogen bonding interaction by aromatic-π contacts, and the ADMET (absorption, distribution, metabolism, and excretion) analysis of best leads indicate nontoxic in nature with good potential for drug development. PMID:25848225
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CAD system for footwear design based on whole real 3D data of last surface
NASA Astrophysics Data System (ADS)
Song, Wanzhong; Su, Xianyu
2000-10-01
Two major parts of application of CAD in footwear design are studied: the development of last surface; computer-aided design of planar shoe-template. A new quasi-experiential development algorithm of last surface based on triangulation approximation is presented. This development algorithm consumes less time and does not need any interactive operation for precisely development compared with other development algorithm of last surface. Based on this algorithm, a software, SHOEMAKERTM, which contains computer aided automatic measurement, automatic development of last surface and computer aide design of shoe-template has been developed.
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Facial measurements for frame design.
Tang, C Y; Tang, N; Stewart, M C
1998-04-01
Anthropometric data for the purpose of spectacle frame design are scarce in the literature. Definitions of facial features to be measured with existing systems of facial measurement are often not specific enough for frame design and manufacturing. Currently, for individual frame design, experienced personnel collect data with facial rules or instruments. A new measuring system is proposed, making use of a template in the form of a spectacle frame. Upon fitting the template onto a subject, most of the measuring references can be defined. Such a system can be administered by lesser-trained personnel and can be used for researches covering a larger population.
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Bertaccini, Edward J.; Yoluk, Ozge; Lindahl, Erik R.; Trudell, James R.
2013-01-01
Background Anesthetics mediate portions of their activity via modulation of the γ-aminobutyric acid receptor (GABAaR). While its molecular structure remains unknown, significant progress has been made towards understanding its interactions with anesthetics via molecular modeling. Methods The structure of the torpedo acetylcholine receptor (nAChRα), the structures of the α4 and β2 subunits of the human nAChR, the structures of the eukaryotic glutamate-gated chloride channel (GluCl), and the prokaryotic pH sensing channels, from Gloeobacter violaceus and Erwinia chrysanthemi, were aligned with the SAlign and 3DMA algorithms. A multiple sequence alignment from these structures and those of the GABAaR was performed with ClustalW. The Modeler and Rosetta algorithms independently created three-dimensional constructs of the GABAaR from the GluCl template. The CDocker algorithm docked a congeneric series of propofol derivatives into the binding pocket and scored calculated binding affinities for correlation with known GABAaR potentiation EC50’s. Results Multiple structure alignments of templates revealed a clear consensus of residue locations relevant to anesthetic effects except for torpedo nAChR. Within the GABAaR models generated from GluCl, the residues notable for modulating anesthetic action within transmembrane segments 1, 2, and 3 converged on the intersubunit interface between alpha and beta subunits. Docking scores of a propofol derivative series into this binding site showed strong linear correlation with GABAaR potentiation EC50. Conclusion Consensus structural alignment based on homologous templates revealed an intersubunit anesthetic binding cavity within the transmembrane domain of the GABAaR, which showed correlation of ligand docking scores with experimentally measured GABAaR potentiation. PMID:23770602
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Bertaccini, Edward J; Yoluk, Ozge; Lindahl, Erik R; Trudell, James R
2013-11-01
Anesthetics mediate portions of their activity via modulation of the γ-aminobutyric acid receptor (GABAaR). Although its molecular structure remains unknown, significant progress has been made toward understanding its interactions with anesthetics via molecular modeling. The structure of the torpedo acetylcholine receptor (nAChRα), the structures of the α4 and β2 subunits of the human nAChR, the structures of the eukaryotic glutamate-gated chloride channel (GluCl), and the prokaryotic pH-sensing channels, from Gloeobacter violaceus and Erwinia chrysanthemi, were aligned with the SAlign and 3DMA algorithms. A multiple sequence alignment from these structures and those of the GABAaR was performed with ClustalW. The Modeler and Rosetta algorithms independently created three-dimensional constructs of the GABAaR from the GluCl template. The CDocker algorithm docked a congeneric series of propofol derivatives into the binding pocket and scored calculated binding affinities for correlation with known GABAaR potentiation EC50s. Multiple structure alignments of templates revealed a clear consensus of residue locations relevant to anesthetic effects except for torpedo nAChR. Within the GABAaR models generated from GluCl, the residues notable for modulating anesthetic action within transmembrane segments 1, 2, and 3 converged on the intersubunit interface between α and β subunits. Docking scores of a propofol derivative series into this binding site showed strong linear correlation with GABAaR potentiation EC50. Consensus structural alignment based on homologous templates revealed an intersubunit anesthetic binding cavity within the transmembrane domain of the GABAaR, which showed a correlation of ligand docking scores with experimentally measured GABAaR potentiation.
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Quantification of rectifications for the Northwestern University Flexible Sub-Ischial Vacuum Socket.
Fatone, Stefania; Johnson, William Brett; Tran, Lilly; Tucker, Kerice; Mowrer, Christofer; Caldwell, Ryan
2017-06-01
The fit and function of a prosthetic socket depend on the prosthetist's ability to design the socket's shape to distribute load comfortably over the residual limb. We recently developed a sub-ischial socket for persons with transfemoral amputation: the Northwestern University Flexible Sub-Ischial Vacuum Socket. This study aimed to quantify the rectifications required to fit the Northwestern University Flexible Sub-Ischial Vacuum Socket to teach the technique to prosthetists as well as provide a computer-aided design-computer-aided manufacturing option. Development project. A program was used to align scans of unrectified and rectified negative molds and calculate shape change as a result of rectification. Averaged rectifications were used to create a socket template, which was shared with a central fabrication facility engaged in provision of Northwestern University Flexible Sub-Ischial Vacuum Sockets to early clinical adopters. Feedback regarding quality of fitting was obtained. Rectification maps created from 30 cast pairs of successfully fit Northwestern University Flexible Sub-Ischial Vacuum Sockets confirmed that material was primarily removed from the positive mold in the proximal-lateral and posterior regions. The template was used to fabricate check sockets for 15 persons with transfemoral amputation. Feedback suggested that the template provided a reasonable initial fit with only minor adjustments. Rectification maps and template were used to facilitate teaching and central fabrication of the Northwestern University Flexible Sub-Ischial Vacuum Socket. Minor issues with quality of initial fit achieved with the template may be due to inability to adjust the template to patient characteristics (e.g. tissue type, limb shape) and/or the degree to which it represented a fully mature version of the technique. Clinical relevance Rectification maps help communicate an important step in the fabrication of the Northwestern University Flexible Sub-Ischial Vacuum Socket facilitating dissemination of the technique, while the average template provides an alternative fabrication option via computer-aided design-computer-aided manufacturing and central fabrication.
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Song, Weiling; Zhang, Qiao; Sun, Wenbo
2015-02-11
An ultrasensitive protocol for fluorescent detection of DNA is designed by combining the template enhanced hybridization process (TEHP) with Rolling Circle Amplification (RCA) and Catalytic Hairpin Assembly (CHA), showing a remarkable amplification efficiency.
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NASA Astrophysics Data System (ADS)
Yu, Shuang; Sui, Jing-jing; Xu, Jing; Ding, Yi-hong
2018-05-01
Contrasting the big family of the planar tetracoordinate carbon (ptC), species featuring the planar tetracoordinate heavier group element M (ptM) have been largely limited. Effective structural frameworks to accommodate such ptM centres are thus highly desired. In the present article, we report an extensive computational study on 60 pentatomic systems C2X2Yq (X=Si,Ge,Sn,Pb; Y=C,Si,Ge,Sn,Pb; q = +1,0,-1) covering both the low and high spin states. Up to 34 systems were shown to have the very low-lying singlet planar tetracoordinate heavier group 14 (ptM with M=Si,Ge,Sn,Pb) structures bearing the 19 (q = +1), 20 (q = 0) and 21 (q = -1) valence electrons (ve). Structural and bonding analysis confirmed the effectiveness of the inherent π-type ligand skeleton XCCX or XCCY that each have several sets of π-bonding orbitals to stabilise the ptM centre. The structural and bonding motifs of these ptMs differ greatly from the classic ptMs, which have the σ-type ligand skeleton, smaller number of valence electrons (≤18ve), and the centre → ligand π-delocalisation.
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Structure-based discovery and binding site analysis of histamine receptor ligands.
Kiss, Róbert; Keserű, György M
2016-12-01
The application of structure-based drug discovery in histamine receptor projects was previously hampered by the lack of experimental structures. The publication of the first X-ray structure of the histamine H1 receptor has been followed by several successful virtual screens and binding site analysis studies of H1-antihistamines. This structure together with several other recently solved aminergic G-protein coupled receptors (GPCRs) enabled the development of more realistic homology models for H2, H3 and H4 receptors. Areas covered: In this paper, the authors review the development of histamine receptor models and their application in drug discovery. Expert opinion: In the authors' opinion, the application of atomistic histamine receptor models has played a significant role in understanding key ligand-receptor interactions as well as in the discovery of novel chemical starting points. The recently solved H1 receptor structure is a major milestone in structure-based drug discovery; however, our analysis also demonstrates that for building H3 and H4 receptor homology models, other GPCRs may be more suitable as templates. For these receptors, the authors envisage that the development of higher quality homology models will significantly contribute to the discovery and optimization of novel H3 and H4 ligands.
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The systematic annotation of the three main GPCR families in Reactome.
Jassal, Bijay; Jupe, Steven; Caudy, Michael; Birney, Ewan; Stein, Lincoln; Hermjakob, Henning; D'Eustachio, Peter
2010-07-29
Reactome is an open-source, freely available database of human biological pathways and processes. A major goal of our work is to provide an integrated view of cellular signalling processes that spans from ligand-receptor interactions to molecular readouts at the level of metabolic and transcriptional events. To this end, we have built the first catalogue of all human G protein-coupled receptors (GPCRs) known to bind endogenous or natural ligands. The UniProt database has records for 797 proteins classified as GPCRs and sorted into families A/1, B/2 and C/3 on the basis of amino acid sequence. To these records we have added details from the IUPHAR database and our own manual curation of relevant literature to create reactions in which 563 GPCRs bind ligands and also interact with specific G-proteins to initiate signalling cascades. We believe the remaining 234 GPCRs are true orphans. The Reactome GPCR pathway can be viewed as a detailed interactive diagram and can be exported in many forms. It provides a template for the orthology-based inference of GPCR reactions for diverse model organism species, and can be overlaid with protein-protein interaction and gene expression datasets to facilitate overrepresentation studies and other forms of pathway analysis. Database URL: http://www.reactome.org.
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NASA Astrophysics Data System (ADS)
Wang, Fangfang; Zhou, Bo
2018-04-01
Protein tyrosine phosphatase 1B (PTP1B) is an intracellular non-receptor phosphatase that is implicated in signal transduction of insulin and leptin pathways, thus PTP1B is considered as potential target for treating type II diabetes and obesity. The present article is an attempt to formulate the three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling of a series of compounds possessing PTP1B inhibitory activities using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. The optimum template ligand-based models are statistically significant with great CoMFA (R2cv = 0.600, R2pred = 0.6760) and CoMSIA (R2cv = 0.624, R2pred = 0.8068) values. Molecular docking was employed to elucidate the inhibitory mechanisms of this series of compounds against PTP1B. In addition, the CoMFA and CoMSIA field contour maps agree well with the structural characteristics of the binding pocket of PTP1B active site. The knowledge of structure-activity relationship and ligand-receptor interactions from 3D-QSAR model and molecular docking will be useful for better understanding the mechanism of ligand-receptor interaction and facilitating development of novel compounds as potent PTP1B inhibitors.
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A Strategy for Reusing the Data of Electronic Medical Record Systems for Clinical Research.
Matsumura, Yasushi; Hattori, Atsushi; Manabe, Shiro; Tsuda, Tsutomu; Takeda, Toshihiro; Okada, Katsuki; Murata, Taizo; Mihara, Naoki
2016-01-01
There is a great need to reuse data stored in electronic medical records (EMR) databases for clinical research. We previously reported the development of a system in which progress notes and case report forms (CRFs) were simultaneously recorded using a template in the EMR in order to exclude redundant data entry. To make the data collection process more efficient, we are developing a system in which the data originally stored in the EMR database can be populated within a frame in a template. We developed interface plugin modules that retrieve data from the databases of other EMR applications. A universal keyword written in a template master is converted to a local code using a data conversion table, then the objective data is retrieved from the corresponding database. The template element data, which are entered by a template, are stored in the template element database. To retrieve the data entered by other templates, the objective data is designated by the template element code with the template code, or by the concept code if it is written for the element. When the application systems in the EMR generate documents, they also generate a PDF file and a corresponding document profile XML, which includes important data, and send them to the document archive server and the data sharing saver, respectively. In the data sharing server, the data are represented by an item with an item code with a document class code and its value. By linking a concept code to an item identifier, an objective data can be retrieved by designating a concept code. We employed a flexible strategy in which a unique identifier for a hospital is initially attached to all of the data that the hospital generates. The identifier is secondarily linked with concept codes. The data that are not linked with a concept code can also be retrieved using the unique identifier of the hospital. This strategy makes it possible to reuse any of a hospital's data.
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2014-01-01
Background This study aimed to evaluate the accuracy of surgical outcomes in free iliac crest mandibular reconstructions that were carried out with virtual surgical plans and rapid prototyping templates. Methods This study evaluated eight patients who underwent mandibular osteotomy and reconstruction with free iliac crest grafts using virtual surgical planning and designed guiding templates. Operations were performed using the prefabricated guiding templates. Postoperative three-dimensional computer models were overlaid and compared with the preoperatively designed models in the same coordinate system. Results Compared to the virtual osteotomy, the mean error of distance of the actual mandibular osteotomy was 2.06 ± 0.86 mm. When compared to the virtual harvested grafts, the mean error volume of the actual harvested grafts was 1412.22 ± 439.24 mm3 (9.12% ± 2.84%). The mean error between the volume of the actual harvested grafts and the shaped grafts was 2094.35 ± 929.12 mm3 (12.40% ± 5.50%). Conclusions The use of computer-aided rapid prototyping templates for virtual surgical planning appears to positively influence the accuracy of mandibular reconstruction. PMID:24957053
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Yang, Wanggui; Chen, Yali; Wong, Man Shing; Lo, Pik Kwan
2012-10-08
One of the most important criteria for the successful DNA-templated polymerization to generate fully synthetic biomimetic polymers is to design the complementary structural monomers, which assemble to the templates strongly and precisely before carrying polymerization. In this study, water-soluble, laterally thymine-substituted donor-acceptor π-conjugated molecules were designed and synthesized to self-assemble with complementary oligoadenines templates, dA(20) and dA(40), into stable and tubular assemblies through noncovalent interactions including π-π stacking, dipole-dipole interactions, and the complementary adenine-thymine (A-T) hydrogen-bonding. UV-vis, fluorescence, circular dichroism (CD), atomic force microscopy (AFM), and transmission electron microscopy (TEM) techniques were used to investigate the formation of highly robust nanofibrous structures. Our results have demonstrated for the first time that the dipole-dipole interactions are stronger and useful to reinforce the assembly of donor-acceptor π-conjugated molecules to DNA templates and the formation of the stable and robust supramolecular nanofibrous complexes together with the complementary hydrogen bonding interactions. This provides an initial step toward DNA-templated polymerization to create fully synthetic DNA-mimetic polymers for biotechnological applications. This study also presents an opportunity to precisely position donor-acceptor type molecules in a controlled manner and tailor-make advanced materials for various biotechnological applications.
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Graf, Neil J; Bowser, Michael T
2013-10-07
Two different fabrication methods were employed to fabricate micropumps with different cross-sectional channel geometries. The first was to fabricate rectangular cross-sectional microchannel geometries using the well known fabrication method of replica molding (REM). The second, and far less utilized fabrication technique, was to create microchannel molds using an in-house fabricated handheld micro injection molding apparatus. The injection mold apparatus was designed for use with elastomeric room temperature vulcanization (RTV) polymers, as opposed to most other injection molding machines, which are designed for use with thermoplastic polymers. The injection mold's bottom plate was used as a microchannel molding template. The molding template was created by threading a small-diameter wire (150 μm or less) through the injection mold's bottom plate, with subsequent adhesion and smoothing of a thin piece of aluminum foil over the wire-raised injection mold template. When molded against, the template produced a rounded/Gaussian-shaped PDMS microchannel. The design of the injection mold will be presented, along with a direct comparison for micropump performance metrics such as flow rate, valving characteristics, and maximum backpressures attainable for each of the respective micropump channel geometries.
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Application of 3D-QSAR in the rational design of receptor ligands and enzyme inhibitors.
Mor, Marco; Rivara, Silvia; Lodola, Alessio; Lorenzi, Simone; Bordi, Fabrizio; Plazzi, Pier Vincenzo; Spadoni, Gilberto; Bedini, Annalida; Duranti, Andrea; Tontini, Andrea; Tarzia, Giorgio
2005-11-01
Quantitative structure-activity relationships (QSARs) are frequently employed in medicinal chemistry projects, both to rationalize structure-activity relationships (SAR) for known series of compounds and to help in the design of innovative structures endowed with desired pharmacological actions. As a difference from the so-called structure-based drug design tools, they do not require the knowledge of the biological target structure, but are based on the comparison of drug structural features, thus being defined ligand-based drug design tools. In the 3D-QSAR approach, structural descriptors are calculated from molecular models of the ligands, as interaction fields within a three-dimensional (3D) lattice of points surrounding the ligand structure. These descriptors are collected in a large X matrix, which is submitted to multivariate analysis to look for correlations with biological activity. Like for other QSARs, the reliability and usefulness of the correlation models depends on the validity of the assumptions and on the quality of the data. A careful selection of compounds and pharmacological data can improve the application of 3D-QSAR analysis in drug design. Some examples of the application of CoMFA and CoMSIA approaches to the SAR study and design of receptor or enzyme ligands is described, pointing the attention to the fields of melatonin receptor ligands and FAAH inhibitors.
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Smirnov, Ivan; Carletti, Eugénie; Kurkova, Inna; Nachon, Florian; Nicolet, Yvain; Mitkevich, Vladimir A.; Débat, Hélène; Avalle, Bérangère; Belogurov, Alexey A.; Kuznetsov, Nikita; Reshetnyak, Andrey; Masson, Patrick; Tonevitsky, Alexander G.; Ponomarenko, Natalia; Makarov, Alexander A.; Friboulet, Alain; Tramontano, Alfonso; Gabibov, Alexander
2011-01-01
Igs offer a versatile template for combinatorial and rational design approaches to the de novo creation of catalytically active proteins. We have used a covalent capture selection strategy to identify biocatalysts from within a human semisynthetic antibody variable fragment library that uses a nucleophilic mechanism. Specific phosphonylation at a single tyrosine within the variable light-chain framework was confirmed in a recombinant IgG construct. High-resolution crystallographic structures of unmodified and phosphonylated Fabs display a 15-Å-deep two-chamber cavity at the interface of variable light (VL) and variable heavy (VH) fragments having a nucleophilic tyrosine at the base of the site. The depth and structure of the pocket are atypical of antibodies in general but can be compared qualitatively with the catalytic site of cholinesterases. A structurally disordered heavy chain complementary determining region 3 loop, constituting a wall of the cleft, is stabilized after covalent modification by hydrogen bonding to the phosphonate tropinol moiety. These features and presteady state kinetics analysis indicate that an induced fit mechanism operates in this reaction. Mutations of residues located in this stabilized loop do not interfere with direct contacts to the organophosphate ligand but can interrogate second shell interactions, because the H3 loop has a conformation adjusted for binding. Kinetic and thermodynamic parameters along with computational docking support the active site model, including plasticity and simple catalytic components. Although relatively uncomplicated, this catalytic machinery displays both stereo- and chemical selectivity. The organophosphate pesticide paraoxon is hydrolyzed by covalent catalysis with rate-limiting dephosphorylation. This reactibody is, therefore, a kinetically selected protein template that has enzyme-like catalytic attributes. PMID:21896761
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Subbotina, Julia; Yarov-Yarovoy, Vladimir; Lees-Miller, James; Durdagi, Serdar; Guo, Jiqing; Duff, Henry J; Noskov, Sergei Yu
2010-11-01
The hERG1 gene (Kv11.1) encodes a voltage-gated potassium channel. Mutations in this gene lead to one form of the Long QT Syndrome (LQTS) in humans. Promiscuous binding of drugs to hERG1 is known to alter the structure/function of the channel leading to an acquired form of the LQTS. Expectably, creation and validation of reliable 3D model of the channel have been a key target in molecular cardiology and pharmacology for the last decade. Although many models were built, they all were limited to pore domain. In this work, a full model of the hERG1 channel is developed which includes all transmembrane segments. We tested a template-driven de-novo design with ROSETTA-membrane modeling using side-chain placements optimized by subsequent molecular dynamics (MD) simulations. Although backbone templates for the homology modeled parts of the pore and voltage sensors were based on the available structures of KvAP, Kv1.2 and Kv1.2-Kv2.1 chimera channels, the missing parts are modeled de-novo. The impact of several alignments on the structure of the S4 helix in the voltage-sensing domain was also tested. Herein, final models are evaluated for consistency to the reported structural elements discovered mainly on the basis of mutagenesis and electrophysiology. These structural elements include salt bridges and close contacts in the voltage-sensor domain; and the topology of the extracellular S5-pore linker compared with that established by toxin foot-printing and nuclear magnetic resonance studies. Implications of the refined hERG1 model to binding of blockers and channels activators (potent new ligands for channel activations) are discussed. © 2010 Wiley-Liss, Inc.
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Rubina, Marina; Sherrill, William M; Barkov, Alexey Yu
2014-01-01
Summary A novel class of chiral phosphanyl-oxazoline (PHOX) ligands with a conformationally rigid cyclopropyl backbone was synthesized and tested in the intermolecular asymmetric Heck reaction. Mechanistic modelling and crystallographic studies were used to predict the optimal ligand structure and helped to design a very efficient and highly selective catalytic system. Employment of the optimized ligands in the asymmetric arylation of cyclic olefins allowed for achieving high enantioselectivities and significantly suppressing product isomerization. Factors affecting the selectivity and the rate of the isomerization were identified. It was shown that the nature of this isomerization is different from that demonstrated previously using chiral diphosphine ligands. PMID:25161709
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Design challenges in nanoparticle-based platforms: Implications for targeted drug delivery systems
NASA Astrophysics Data System (ADS)
Mullen, Douglas Gurnett
Characterization and control of heterogeneous distributions of nanoparticle-ligand components are major design challenges for nanoparticle-based platforms. This dissertation begins with an examination of poly(amidoamine) (PAMAM) dendrimer-based targeted delivery platform. A folic acid targeted modular platform was developed to target human epithelial cancer cells. Although active targeting was observed in vitro, active targeting was not found in vivo using a mouse tumor model. A major flaw of this platform design was that it did not provide for characterization or control of the component distribution. Motivated by the problems experienced with the modular design, the actual composition of nanoparticle-ligand distributions were examined using a model dendrimer-ligand system. High Pressure Liquid Chromatography (HPLC) resolved the distribution of components in samples with mean ligand/dendrimer ratios ranging from 0.4 to 13. A peak fitting analysis enabled the quantification of the component distribution. Quantified distributions were found to be significantly more heterogeneous than commonly expected and standard analytical parameters, namely the mean ligand/nanoparticle ratio, failed to adequately represent the component heterogeneity. The distribution of components was also found to be sensitive to particle modifications that preceded the ligand conjugation. With the knowledge gained from this detailed distribution analysis, a new platform design was developed to provide a system with dramatically improved control over the number of components and with improved batch reproducibility. Using semi-preparative HPLC, individual dendrimer-ligand components were isolated. The isolated dendrimer with precise numbers of ligands were characterized by NMR and analytical HPLC. In total, nine different dendrimer-ligand components were obtained with degrees of purity ≥80%. This system has the potential to serve as a platform to which a precise number of functional molecules can be attached and has the potential to dramatically improve platform efficacy. An additional investigation of reproducibility challenges for current dendrimer-based platform designs is also described. The mass transport quality during the partial acetylation reaction of the dendrimer was found to have a major impact on subsequent dendrimer-ligand distributions that cannot be detected by standard analytical techniques. Consequently, this reaction should be eliminated from the platform design. Finally, optimized protocols for purification and characterization of PAMAM dendrimer were detailed.
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Wallace, A. C.; Borkakoti, N.; Thornton, J. M.
1997-01-01
It is well established that sequence templates such as those in the PROSITE and PRINTS databases are powerful tools for predicting the biological function and tertiary structure for newly derived protein sequences. The number of X-ray and NMR protein structures is increasing rapidly and it is apparent that a 3D equivalent of the sequence templates is needed. Here, we describe an algorithm called TESS that automatically derives 3D templates from structures deposited in the Brookhaven Protein Data Bank. While a new sequence can be searched for sequence patterns, a new structure can be scanned against these 3D templates to identify functional sites. As examples, 3D templates are derived for enzymes with an O-His-O "catalytic triad" and for the ribonucleases and lysozymes. When these 3D templates are applied to a large data set of nonidentical proteins, several interesting hits are located. This suggests that the development of a 3D template database may help to identify the function of new protein structures, if unknown, as well as to design proteins with specific functions. PMID:9385633
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Luckett, Tim; Bhattarai, Priyanka; Phillips, Jane; Agar, Meera; Currow, David; Krastev, Yordanka; Davidson, Patricia M
2015-11-01
A drive to promote advance care planning at a population level has led to a proliferation of online advance care directive (ACD) templates but little information to guide consumer choice. The current study aimed to appraise the quality of online ACD templates promoted for use in Australia. A systematic review of online Australian ACD templates was conducted in February 2014. ACD templates were identified via Google searches, and quality was independently appraised by two reviewers against criteria from the 2011 report A National Frameworkfor Advance Care Directives. Bias either towards or against future medical treatment was assessed using criteria designed to limit subjectivity. Fourteen online ACD templates were included, all of which were available only in English. Templates developed by Southern Cross University best met the framework criteria. One ACD template was found to be biased against medical treatment--the Dying with Dignity Victoria Advance Healthcare Directive. More research is needed to understand how online resources can optimally elicit and record consumers' individual preferences for future care. Future iterations of the framework should address online availability and provide a simple rating system to inform choice and drive quality improvement.
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NASA Astrophysics Data System (ADS)
Ferebee, Rachel L.
The broader technical objective of this work is to contribute to the development of enzyme-functionalized nanoporous membranes that can function as autonomous and target selective dynamic separators. The scientific objective of the research performed within this thesis is to elucidate the parameters that control the mixing of proteins in organic host materials and in block copolymers templates in particular. A "biomimetic" membrane system that uses enzymes to selectively neutralize targets and trigger a change in permeability of nanopores lined with a pH-responsive polymer has been fabricated and characterized. Mechanical and functional stability, as well as scalability, have been demonstrated for this system. Additional research has focused on the role of polymeric ligands on the solubility characteristics of the model protein, Bovine Serum Albumin (BSA). For this purpose BSA was conjugated with poly(ethylene glycol) (PEG) ligands of varied degree of polymerization and grafting density. Combined static and dynamic light scattering was used (in conjunction with MALDI-TOF) to determine the second virial coefficient in PBS solutions. At a given mass fraction PEG or average number of grafts, the solubility of BSA-PEG conjugates is found to increase with the degree of polymerization of conjugated PEG. This result informs the synthesis of protein-conjugate systems that are optimized for the fabrication of block copolymer blend materials with maximum protein loading. Blends of BSA-PEG conjugates and block copolymer (BCP) matrices were fabricated to evaluate the dispersion morphology and solubility limits in a model system. Electron microscopy was used to evaluate the changes in lamellar spacing with increased filling fraction of BSA-PEG conjugates.
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Ligand-Enabled meta-C–H Activation Using a Transient Mediator
Wang, Xiao-Chen; Gong, Wei; Fang, Li-Zhen; Zhu, Ru-Yi; Li, Suhua; Engle, Keary M.; Yu, Jin-Quan
2015-01-01
Achieving site selectivity in C–H functionalization reactions is a significant challenge, especially when the target C–H bond is distant from existing functional groups.1–5 Coordination of a functional group to a metal catalyst is often a key driving force and control element in many important reactions including asymmetric hydrogenation,6 epoxidation7, 8, and lithiation9. Exploitation of this effect has led to the development of a broad range of directed C–H activation reactions.10–14 However, such C–H activation methods are limited to proximal C–H bonds, which are spatially and geometrically accessible from the directing functional group. Development of meta-selective C–H functionalizations remains a significant challenge.1–5,15–17 We recently developed a U- shaped template that can be used to overcome this constraint and have shown that it can be used to selectively activate remote meta-C–H bonds.1, 2 While this approach has proven applicable for a diverse set of substrates and catalytic transformations,3–5 the need for a covalently attached complex template is a significant drawback for synthetic applications. In this manuscript, we report an alternative approach, one that employs norbornene as a transient mediator to achieve meta-selective C–H activation with a simple and common ortho-directing group. The use of a newly developed pyridine-based ligand is crucial for relaying the palladium catalyst to the meta position by norbornene following initial ortho- C–H activation. Thus, this catalytic reaction demonstrates the feasibility of switching ortho-selectivity to meta-selectivity in C–H activation of the same substrate by catalyst control. PMID:25754328
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Hunter-Smith, David J.; Rostek, Marie; Smith, Julian A.; Rozen, Warren Matthew
2018-01-01
Summary: Optimizing preoperative planning is widely sought in deep inferior epigastric artery perforator (DIEP) flap surgery. One reason for this is that rates of fat necrosis remain relatively high (up to 35%), and that adjusting flap design by an improved understanding of individual perforasomes and perfusion characteristics may be useful in reducing the risk of fat necrosis. Imaging techniques have substantially improved over the past decade, and with recent advances in 3D printing, an improved demonstration of imaged anatomy has become available. We describe a 3D-printed template that can be used preoperatively to mark out a patient’s individualized perforasome for flap planning in DIEP flap surgery. We describe this “perforasome template” technique in a case of a 46-year-old woman undergoing immediate unilateral breast reconstruction with a DIEP flap. Routine preoperative computed tomographic angiography was performed, with open-source software (3D Slicer, Autodesk MeshMixer and Cura) and a desktop 3D printer (Ultimaker 3E) used to create a template used to mark intra-flap, subcutaneous branches of deep inferior epigastric artery (DIEA) perforators on the abdomen. An individualized 3D printed template was used to estimate the size and boundaries of a perforasome and perfusion map. The information was used to aid flap design. We describe a new technique of 3D printing a patient-specific perforasome template that can be used preoperatively to infer perforasomes and aid flap design. PMID:29464169
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Yuan Yanping; Wang Ruiyao; Kong Deyuan
2005-06-15
The first organically templated 3d-4f mixed metal sulfates, [H{sub 2}en]{sub 2}{l_brace}La{sub 2}M(SO{sub 4}){sub 6}(H{sub 2}O){sub 2}{r_brace} (M=Co 1, Ni 2) have been synthesized and structurally determined from non-merohedrally twinned crystals. The two compounds are isostructural and their structures feature a three-dimensional anionic network formed by the lanthanum(III) and nickel(II) ions bridged by sulfate anions. The La(III) ions in both compounds are 10-coordinated by four sulfate anions in bidentate chelating fashion, and two sulfate anions in a unidentate fashion. The transition metal(II) ion is octahedrally coordinated by six oxygens from four sulfate anions and two aqua ligands. The doubly protonated enthylenediaminemore » cations are located at the tunnels formed by 8-membered rings (four La and four sulfate anions)« less
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Size-controlled soft-template synthesis of carbon nanodots toward versatile photoactive materials.
Kwon, Woosung; Lee, Gyeongjin; Do, Sungan; Joo, Taiha; Rhee, Shi-Woo
2014-02-12
Size-controlled soft-template synthesis of carbon nanodots (CNDs) as novel photoactive materials is reported. The size of the CNDs can be controlled by regulating the amount of an emulsifier. As the size increases, the CNDs exhibit blue-shifted photoluminescence (PL) or so-called an inverse PL shift. Using time-correlated single photon counting, ultraviolet photoelectron spectroscopy, and low-temperature PL measurements, it is revealed that the CNDs are composed of sp² clusters with certain energy gaps and their oleylamine ligands act as auxochromes to reduce the energy gaps. This insight can provide a plausible explanation on the origin of the inverse PL shift which has been debatable over a past decade. To explore the potential of the CNDs as photoactive materials, several prototypes of CND-based optoelectronic devices, including multicolored light-emitting diodes and air-stable organic solar cells, are demonstrated. This study could shed light on future applications of the CNDs and further expedite the development of other related fields. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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The impact of domain knowledge on structured data collection and templated note design.
Windle, T; McClay, J C; Windle, J R
2013-01-01
The objective of this case report is to evaluate the importance of specialized domain knowledge when designing and using structured templated notes in a clinical environment. To analyze the impact of specialization on structured note generation we compared notes generated for three scenarios: 1) We compared the templated history of present illness (HPI) for patients presenting with a dermatology concern to the dermatologist versus the emergency department. 2) We compared the evaluation of chest pain by ED physicians versus cardiologists. 3) Finally, we compared the data elements asked for in the evaluation of the gastrointestinal system between cardiologists and the liver transplant service (LTS). We used the SNOMED CT representation via BioPortal to evaluate specificity and grouping between data elements and specialized physician groups. We found few similarities in structured data elements designed by and for the specific physician groups. The distinctness represented both differences in granularity as well as fundamental differences in data elements requested. When compared to ED physicians, dermatologists had different and more granular elements while cardiologists requested much more granular data. Comparing cardiologists and LTS, there were differences in the data elements requested. This case study supports the importance of domain knowledge in EHR design and implementation. That different specialities should want and use different information is well supported by cognitive science literature. Despite this, it is rare for domain knowledge to be considered in EHR implementation. Physicians with correct domain knowledge should be involved in the design process of templated notes.
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Potapov, V; Reichmann, D; Abramovich, R; Filchtinski, D; Zohar, N; Ben Halevy, D; Edelman, M; Sobolev, V; Schreiber, G
2008-12-05
A new method is presented for the redesign of protein-protein interfaces, resulting in specificity of the designed pair while maintaining high affinity. The design is based on modular interface architecture and was carried out on the interaction between TEM1 beta-lactamase and its inhibitor protein, beta-lactamase inhibitor protein. The interface between these two proteins is composed of several mostly independent modules. We previously showed that it is possible to delete a complete module without affecting the overall structure of the interface. Here, we replace a complete module with structure fragments taken from nonrelated proteins. Nature-optimized fragments were chosen from 10(7) starting templates found in the Protein Data Bank. A procedure was then developed to identify sets of interacting template residues with a backbone arrangement mimicking the original module. This generated a final list of 361 putative replacement modules that were ranked using a novel scoring function based on grouped atom-atom contact surface areas. The top-ranked designed complex exhibited an affinity of at least the wild-type level and a mode of binding that was remarkably specific despite the absence of negative design in the procedure. In retrospect, the combined application of three factors led to the success of the design approach: utilizing the modular construction of the interface, capitalizing on native rather than artificial templates, and ranking with an accurate atom-atom contact surface scoring function.
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Designing ligands to bind proteins
Whitesides, George M.; Krishnamurthy, Vijay M.
2009-01-01
The ability to design drugs (so-called ‘rational drug design’) has been one of the long-term objectives of chemistry for 50 years. It is an exceptionally difficult problem, and many of its parts lie outside the expertise of chemistry. The much more limited problem – how to design tight-binding ligands (rational ligand design) – would seem to be one that chemistry could solve, but has also proved remarkably recalcitrant. The question is ‘Why is it so difficult?’ and the answer is ‘We still don't entirely know’. This perspective discusses some of the technical issues – potential functions, protein plasticity, enthalpy/entropy compensation, and others – that contribute, and suggests areas where fundamental understanding of protein–ligand interactions falls short of what is needed. It surveys recent technological developments (in particular, isothermal titration calorimetry) that will, hopefully, make now the time for serious progress in this area. It concludes with the calorimetric examination of the association of a series of systematically varied ligands with a model protein. The counterintuitive thermodynamic results observed serve to illustrate that, even in relatively simple systems, understanding protein–ligand association is challenging. PMID:16817982
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"Cloud" functions and templates of engineering calculations for nuclear power plants
NASA Astrophysics Data System (ADS)
Ochkov, V. F.; Orlov, K. A.; Ko, Chzho Ko
2014-10-01
The article deals with an important problem of setting up computer-aided design calculations of various circuit configurations and power equipment carried out using the templates and standard computer programs available in the Internet. Information about the developed Internet-based technology for carrying out such calculations using the templates accessible in the Mathcad Prime software package is given. The technology is considered taking as an example the solution of two problems relating to the field of nuclear power engineering.
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Integrating structure-based and ligand-based approaches for computational drug design.
Wilson, Gregory L; Lill, Markus A
2011-04-01
Methods utilized in computer-aided drug design can be classified into two major categories: structure based and ligand based, using information on the structure of the protein or on the biological and physicochemical properties of bound ligands, respectively. In recent years there has been a trend towards integrating these two methods in order to enhance the reliability and efficiency of computer-aided drug-design approaches by combining information from both the ligand and the protein. This trend resulted in a variety of methods that include: pseudoreceptor methods, pharmacophore methods, fingerprint methods and approaches integrating docking with similarity-based methods. In this article, we will describe the concepts behind each method and selected applications.
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Biomimetic/Bioinspired Design of Enzyme@capsule Nano/Microsystems.
Shi, J; Jiang, Y; Zhang, S; Yang, D; Jiang, Z
2016-01-01
Enzyme@capsule nano/microsystems, which refer to the enzyme-immobilized capsules, have received tremendous interest owing to the combination of the high catalytic activities of encapsulated enzymes and the hierarchical structure of the capsule. The preparation of capsules and simultaneous encapsulation of enzymes is recognized as the core process for the rational design and construction of enzyme@capsule nano/microsystems. The strategy used has three major steps: (a) generation of the templates, (b) surface coating on the templates, and (c) removal of the templates, and it has been proven to be effective and versatile for the construction of enzyme@capsule nano/microsystems. Several conventional methods, including layer-by-layer assembly of polyelectrolytes, liquid crystalline templating method, etc., were used to design and construct enzyme@capsule nano/microsystems, but these have two major drawbacks. One is the low mechanical stability of the systems and the second is the harsh conditions used in the construction process. Learning from nature, several biomimetic/bioinspired methods such as biomineralization, biomimetic/bioinspired adhesion, and their combination have been exploited for the construction of enzyme@capsule nano/microsystems. In this chapter, we will present a general protocol for the construction of enzyme@capsule nano/microsystems using the latter approach. Some suggestions for improved design, construction, and characterization will also be presented with detailed procedures for specific examples. © 2016 Elsevier Inc. All rights reserved.
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The Retinoid X Receptors and Their Ligands
Dawson, Marcia I.; Xia, Zebin
2014-01-01
This chapter presents an overview of the current status of studies on the structural and molecular biology of the retinoid X receptor subtypes α, β, and γ (RXRs, NR2B1–3), their nuclear and cytoplasmic functions, post-transcriptional processing, and recently reported ligands. Points of interest are the different changes in the ligand-binding pocket induced by variously shaped agonists, the communication of the ligand–bound pocket with the coactivator binding surface and the heterodimerization interface, and recently identified ligands that are natural products, those that function as environmental toxins or drugs that had been originally designed to interact with other targets, as well as those that were deliberately designed as RXR-selective transcriptional agonists, synergists, or antagonists. Of these synthetic ligands, the general trend in design appears to be away from fully aromatic rigid structures to those containing partial elements of the flexible tetraene side chain of 9-cis-retinoic acid. PMID:22020178
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Template Authoring Environment for the Automatic Generation of Narrative Content
ERIC Educational Resources Information Center
Caropreso, Maria Fernanda; Inkpen, Diana; Keshtkar, Fazel; Khan, Shahzad
2012-01-01
Natural Language Generation (NLG) systems can make data accessible in an easily digestible textual form; but using such systems requires sophisticated linguistic and sometimes even programming knowledge. We have designed and implemented an environment for creating and modifying NLG templates that requires no programming knowledge, and can operate…
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DOT National Transportation Integrated Search
2013-04-30
A template of pre-crash scenarios is presented to depict national crash statistics and kinematic information of time-to-collision for the design of appropriate crash countermeasures based on vehicle-to-vehicle (V2V) communications. This template serv...
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77 FR 25482 - Proposed Data Collections Submitted for Public Comment and Recommendations
Federal Register 2010, 2011, 2012, 2013, 2014
2012-04-30
... (exp. 1/31/2013). The interview template has been revised to include four additional questions related... residing within participating jurisdictions are interviewed using locally designed interview templates... factors and clinical history of persons with gonorrhea. Each of the 12 sites will interview 60 persons...
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Zhang, Yuan Z; Chen, Bin; Lu, Sheng; Yang, Yong; Zhao, Jian M; Liu, Rui; Li, Yan B; Pei, Guo X
2011-12-01
The considerable variation in anatomical abnormalities of hip joints associated with different types of developmental dysplasia of hip (DDH) makes reconstruction in total hip arthroplasty (THA) difficult. It is desirable to create patient-specific designs for THA procedures. In the cases of adult single DDH, an accuracy-improved method has been developed for acetabular cup prosthesis implantation of hip arthroplasty. From October 2007 to November 2008, 22 patients with single DDH (according to the Crowe standard, all dysplasia hips were classified as type I) were scanned with spiral CT pre-operatively. These patients scheduled for THA were randomly assigned to undergo either conventional THA (control group, n = 11) or navigation template implantation (NT group, n = 11). In the NT group, three-dimensional (3D) CT pelvis image data were transferred to a computer workstation and 3D models of the hip were reconstructed using the Mimics software. The 3D models were then processed by the Imageware software. In brief, a template that best fitted the location and shape of the acetabular cup was 'reversely' built from the 3D model, the rotation centre of the pathological hip determined by mirroring that of the healthy site, and a guiding hole in the template was then designed. The navigational templates were manufactured using a rapid prototyping machine. These navigation templates guide acetabular component placement. Based on the predetermined abduction angle 45° and anteversion angle 18°, after 1 year follow-up, the NT group showed significantly smaller differences (1.6° ± 0.4°, 1.9° ± 1.1°) from the predetermined angles than those in the control group (5.8° ± 2.9°, 3.9° ± 2.5°) (P < 0.05). The template designs facilitated accurate placement of acetabular components in dysplasia of acetabulum. The hip's center of rotation in DDH could be established using computer-aided design, which provides a useful method for the accurate location of prosthesis with a low cost-performance ratio without excessive technical workload on the surgical team. Copyright © 2011 John Wiley & Sons, Ltd.
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Molecular modelling studies on the ORL1-receptor and ORL1-agonists
NASA Astrophysics Data System (ADS)
Bröer, Britta M.; Gurrath, Marion; Höltje, Hans-Dieter
2003-11-01
The ORL1 ( opioid receptor like 1)- receptor is a member of the family of rhodopsin-like G protein-coupled receptors (GPCR) and represents an interesting new therapeutical target since it is involved in a variety of biomedical important processes, such as anxiety, nociception, feeding, and memory. In order to shed light on the molecular basis of the interactions of the GPCR with its ligands, the receptor protein and a dataset of specific agonists were examined using molecular modelling methods. For that purpose, the conformational space of a very potent non-peptide ORL1-receptor agonist (Ro 64-6198) with a small number of rotatable bonds was analysed in order to derive a pharmacophoric arrangement. The conformational analyses yielded a conformation that served as template for the superposition of a set of related analogues. Structural superposition was achieved by employing the program FlexS. Using the experimental binding data and the superposition of the ligands, a 3D-QSAR analysis applying the GRID/GOLPE method was carried out. After the ligand-based modelling approach, a 3D model of the ORL1-receptor has been constructed using homology modelling methods based on the crystal structure of bovine rhodopsin. A representative structure of the model taken from molecular dynamics simulations was used for a manual docking procedure. Asp-130 and Thr-305 within the ORL1-receptor model served as important hydrophilic interaction partners. Furthermore, a hydrophobic cavity was identified stabilizing the agonists within their binding site. The manual docking results were supported using FlexX, which identified the same protein-ligand interaction points.
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In silico ligand binding studies of cyanogenic β-glucosidase, dhurrinase-2 from Sorghum bicolor.
Mahajan, Chavi; Patel, Krunal; Khan, Bashir M; Rawal, Shuban S
2015-07-01
Dhurrinase, a cyanogenic β-glucosidase from Sorghum bicolor is the key enzyme responsible for the hydrolysis of dhurrin to produce toxic hydrogen cyanide, as a part of plant defence mechanism. Dhurrinase 1 (SbDhr1) and dhurrinase 2 (SbDhr2), two isozymes have been isolated and characterized from S. bicolor. However, there is no information in the literature about the three dimensional (3D) structure of SbDhr2 and molecular interactions involved between the protein and ligand. In this study, the three dimensional structure of SbDhr2 was built based on homology modeling by using the X-ray crystallographic structure of its close homologue SbDhr1 as the template. The generated 3D model was energy minimized and the quality was validated by Ramachndran plot, various bioinformatic tools and their relevant parameters. Stability, folding-unfolding and flexibility of the modeled SbDhr2 was evaluated on the basis of RMSD, radius of gyration (Rg) and RMSF values respectively, obtained through molecular dynamic (MD) simulation. Further, molecular docking was performed with its natural substrate dhurrin, one substrate analogue, three un-natural substrates, and one inhibitor. Analysis of molecular interactions in the SbDhr2-ligand complexes revealed the key amino acid residues responsible to stabilize the ligands within the binding pocket through non-bonded interactions and some of them were found to be conserved (Glu239, Tyr381, Trp426, Glu454, Trp511). Reasonably broader substrate specificity of SbDhr2 was explained through the wider entrance passage observed in comparison to SbDhr1.
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Improved Low Temperature Performance of Supercapacitors
NASA Technical Reports Server (NTRS)
Brandon, Erik J.; West, William C.; Smart, Marshall C.; Gnanaraj, Joe
2013-01-01
Low temperature double-layer capacitor operation enabled by: - Base acetonitrile / TEATFB salt formulation - Addition of low melting point formates, esters and cyclic ethers center dot Key electrolyte design factors: - Volume of co-solvent - Concentration of salt center dot Capacity increased through higher capacity electrodes: - Zeolite templated carbons - Asymmetric cell designs center dot Continuing efforts - Improve asymmetric cell performance at low temperature - Cycle life testing Motivation center dot Benchmark performance of commercial cells center dot Approaches for designing low temperature systems - Symmetric cells (activated carbon electrodes) - Symmetric cells (zeolite templated carbon electrodes) - Asymmetric cells (lithium titanate/activated carbon electrodes) center dot Experimental results center dot Summary
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Protein-protein interface analysis and hot spots identification for chemical ligand design.
Chen, Jing; Ma, Xiaomin; Yuan, Yaxia; Pei, Jianfeng; Lai, Luhua
2014-01-01
Rational design for chemical compounds targeting protein-protein interactions has grown from a dream to reality after a decade of efforts. There are an increasing number of successful examples, though major challenges remain in the field. In this paper, we will first give a brief review of the available methods that can be used to analyze protein-protein interface and predict hot spots for chemical ligand design. New developments of binding sites detection, ligandability and hot spots prediction from the author's group will also be described. Pocket V.3 is an improved program for identifying hot spots in protein-protein interface using only an apo protein structure. It has been developed based on Pocket V.2 that can derive receptor-based pharmacophore model for ligand binding cavity. Given similarities and differences between the essence of pharmacophore and hot spots for guiding design of chemical compounds, not only energetic but also spatial properties of protein-protein interface are used in Pocket V.3 for dealing with protein-protein interface. In order to illustrate the capability of Pocket V.3, two datasets have been used. One is taken from ASEdb and BID having experimental alanine scanning results for testing hot spots prediction. The other is taken from the 2P2I database containing complex structures of protein-ligand binding at the original protein-protein interface for testing hot spots application in ligand design.
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A PBOM configuration and management method based on templates
NASA Astrophysics Data System (ADS)
Guo, Kai; Qiao, Lihong; Qie, Yifan
2018-03-01
The design of Process Bill of Materials (PBOM) holds a hinge position in the process of product development. The requirements of PBOM configuration design and management for complex products are analysed in this paper, which include the reuse technique of configuration procedure and urgent management need of huge quantity of product family PBOM data. Based on the analysis, the function framework of PBOM configuration and management has been established. Configuration templates and modules are defined in the framework to support the customization and the reuse of configuration process. The configuration process of a detection sensor PBOM is shown as an illustration case in the end. The rapid and agile PBOM configuration and management can be achieved utilizing template-based method, which has a vital significance to improve the development efficiency for complex products.
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Diehl, Carl; Engström, Olof; Delaine, Tamara; Håkansson, Maria; Genheden, Samuel; Modig, Kristofer; Leffler, Hakon; Ryde, Ulf; Nilsson, Ulf J; Akke, Mikael
2010-10-20
Rational drug design is predicated on knowledge of the three-dimensional structure of the protein-ligand complex and the thermodynamics of ligand binding. Despite the fundamental importance of both enthalpy and entropy in driving ligand binding, the role of conformational entropy is rarely addressed in drug design. In this work, we have probed the conformational entropy and its relative contribution to the free energy of ligand binding to the carbohydrate recognition domain of galectin-3. Using a combination of NMR spectroscopy, isothermal titration calorimetry, and X-ray crystallography, we characterized the binding of three ligands with dissociation constants ranging over 2 orders of magnitude. (15)N and (2)H spin relaxation measurements showed that the protein backbone and side chains respond to ligand binding by increased conformational fluctuations, on average, that differ among the three ligand-bound states. Variability in the response to ligand binding is prominent in the hydrophobic core, where a distal cluster of methyl groups becomes more rigid, whereas methyl groups closer to the binding site become more flexible. The results reveal an intricate interplay between structure and conformational fluctuations in the different complexes that fine-tunes the affinity. The estimated change in conformational entropy is comparable in magnitude to the binding enthalpy, demonstrating that it contributes favorably and significantly to ligand binding. We speculate that the relatively weak inherent protein-carbohydrate interactions and limited hydrophobic effect associated with oligosaccharide binding might have exerted evolutionary pressure on carbohydrate-binding proteins to increase the affinity by means of conformational entropy.
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NASA Astrophysics Data System (ADS)
Wang, Min; Cui, Qi; Sun, Yujie; Wang, Qiao
2018-07-01
In object-based image analysis (OBIA), object classification performance is jointly determined by image segmentation, sample or rule setting, and classifiers. Typically, as a crucial step to obtain object primitives, image segmentation quality significantly influences subsequent feature extraction and analyses. By contrast, template matching extracts specific objects from images and prevents shape defects caused by image segmentation. However, creating or editing templates is tedious and sometimes results in incomplete or inaccurate templates. In this study, we combine OBIA and template matching techniques to address these problems and aim for accurate photovoltaic panel (PVP) extraction from very high-resolution (VHR) aerial imagery. The proposed method is based on the previously proposed region-line primitive association framework, in which complementary information between region (segment) and line (straight line) primitives is utilized to achieve a more powerful performance than routine OBIA. Several novel concepts, including the mutual fitting ratio and best-fitting template based on region-line primitive association analyses, are proposed. Automatic template generation and matching method for PVP extraction from VHR imagery are designed for concept and model validation. Results show that the proposed method can successfully extract PVPs without any user-specified matching template or training sample. High user independency and accuracy are the main characteristics of the proposed method in comparison with routine OBIA and template matching techniques.
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Albumin-stabilized fluorescent silver nanodots
NASA Astrophysics Data System (ADS)
Sych, Tomash; Polyanichko, Alexander; Kononov, Alexei
2017-07-01
Ligand-stabilized Ag nanoclusters (NCs) possess many attractive features including high fluorescence quantum yield, large absorption cross-section, good photostability, large Stokes shift and two-photon absorption cross sections. While plenty of fluorescent clusters have been synthesized on various polymer templates, only a few studies have been reported on the fluorescent Ag clusters on peptides and proteins. We study silver NCs synthesized on different protein matrices, including bovine serum albumin, human serum albumin, egg albumin, equine serum albumin, and lysozyme. Our results show that red-emitting Ag NCs can effectively be stabilized by the disulfide bonds in proteins and that the looser structure of the denatured protein favors formation of the clusters.
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Nuclear Receptors, RXR, and the Big Bang.
Evans, Ronald M; Mangelsdorf, David J
2014-03-27
Isolation of genes encoding the receptors for steroids, retinoids, vitamin D, and thyroid hormone and their structural and functional analysis revealed an evolutionarily conserved template for nuclear hormone receptors. This discovery sparked identification of numerous genes encoding related proteins, termed orphan receptors. Characterization of these orphan receptors and, in particular, of the retinoid X receptor (RXR) positioned nuclear receptors at the epicenter of the "Big Bang" of molecular endocrinology. This Review provides a personal perspective on nuclear receptors and explores their integrated and coordinated signaling networks that are essential for multicellular life, highlighting the RXR heterodimer and its associated ligands and transcriptional mechanism. Copyright © 2014 Elsevier Inc. All rights reserved.
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Chen, Jinyang; Ji, Xinghu; Tinnefeld, Philip; He, Zhike
2016-01-27
In this work, a multifunctional template for selective formation of fluorescent silver nanoclusters (AgNCs) or copper nanoparticles (CuNPs) is put forward. This dumbbell-shaped (DS) DNA template is made up of two cytosine hairpin loops and an adenine-thymine-rich double-helical stem which is closed by the loops. The cytosine loops act as specific regions for the growth of AgNCs, and the double-helical stem serves as template for the CuNPs formation. By carefully investigating the sequence and length of DS DNA, we present the optimal design of the template. Benefiting from the smart design and facile synthesis, a simple, label-free, and ultrasensitive fluorescence strategy for adenosine triphosphate (ATP) detection is proposed. Through the systematic comparison, it is found that the strategy based on CuNPs formation is more sensitive for ATP assay than that based on AgNCs synthesis, and the detection limitation was found to be 81 pM. What's more, the CuNPs formation-based method is successfully applied in the detection of ATP in human serum as well as the determination of cellular ATP. In addition to small target molecule, the sensing strategy was also extended to the detection of biomacromolecule (DNA), which illustrates the generality of this biosensor.
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Qiu, L L; Li, S; Bai, Y X
2016-06-01
To develop surgical templates for orthodontic miniscrew implantation based on cone-beam CT(CBCT)three-dimensional(3D)images and to evaluate the safety and stability of implantation guided by the templates. DICOM data obtained in patients who had CBCT scans taken were processed using Mimics software, and 3D images of teeth and maxillary bone were acquired. Meanwhile, 3D images of miniscrews were acquired using Solidworks software and processed with Mimics software. Virtual position of miniscrews was determined based on 3D images of teeth, bone, and miniscrews. 3D virtual templates were designed according to the virtual implantation plans. STL files were output and the real templates were fabricated with stereolithographic appliance(SLA). Postoperative CBCT scans were used to evaluate the implantation safety and the stability of miniscrews were investigated. All the templates were positioned accurately and kept stable throughout the implantation process. No root damage was found. The deviations were(1.73±0.65)mm at the corona, and(1.28±0.82)mm at the apex, respectively. The stability of miniscrews was fairly well. Surgical templates for miniscrew implantation could be acquired based on 3D CBCT images and fabricated with SLA. Implantation guided by these templates was safe and stable.
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Yu, Jian-Hong; Lo, Lun-Jou; Hsu, Pin-Hsin
2017-01-01
This study integrates cone-beam computed tomography (CBCT)/laser scan image superposition, computer-aided design (CAD), and 3D printing (3DP) to develop a technology for producing customized dental (orthodontic) miniscrew surgical templates using polymer material. Maxillary bone solid models with the bone and teeth reconstructed using CBCT images and teeth and mucosa outer profile acquired using laser scanning were superimposed to allow miniscrew visual insertion planning and permit surgical template fabrication. The customized surgical template CAD model was fabricated offset based on the teeth/mucosa/bracket contour profiles in the superimposition model and exported to duplicate the plastic template using the 3DP technique and polymer material. An anterior retraction and intrusion clinical test for the maxillary canines/incisors showed that two miniscrews were placed safely and did not produce inflammation or other discomfort symptoms one week after surgery. The fitness between the mucosa and template indicated that the average gap sizes were found smaller than 0.5 mm and confirmed that the surgical template presented good holding power and well-fitting adaption. This study addressed integrating CBCT and laser scan image superposition; CAD and 3DP techniques can be applied to fabricate an accurate customized surgical template for dental orthodontic miniscrews. PMID:28280726
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Rational design of mesoporous metals and related nanomaterials by a soft-template approach.
Yamauchi, Yusuke; Kuroda, Kazuyuki
2008-04-07
We review recent developments in the preparation of mesoporous metals and related metal-based nanomaterials. Among the many types of mesoporous materials, mesoporous metals hold promise for a wide range of potential applications, such as in electronic devices, magnetic recording media, and metal catalysts, owing to their metallic frameworks. Mesoporous metals with highly ordered networks and narrow pore-size distributions have traditionally been produced by using mesoporous silica as a hard template. This method involves the formation of an original template followed by deposition of metals within the mesopores and subsequent removal of the template. Another synthetic method is the direct-template approach from lyotropic liquid crystals (LLCs) made of nonionic surfactants at high concentrations. Direct-template synthesis creates a novel avenue for the production of mesoporous metals as well as related metal-based nanomaterials. Many mesoporous metals have been prepared by the chemical or electrochemical reduction of metal salts dissolved in aqueous LLC domains. As a soft template, LLCs are more versatile and therefore more advantageous than hard templates. It is possible to produce various nanostructures (e.g., lamellar, 2D hexagonal (p6mm), and 3D cubic (Ia\\3d)), nanoparticles, and nanotubes simply by controlling the composition of the reaction bath.
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Han, Nanyu; Mu, Yuguang
2013-01-01
Neuraminidase (NA) of influenza is a key target for virus infection control and the recently discovered open 150-cavity in group-1 NA provides new opportunity for novel inhibitors design. In this study, we used a combination of theoretical methods including fragment docking, molecular linking and molecular dynamics simulations to design ligands that specifically target at the 150-cavity. Through in silico screening of a fragment compound library on the open 150-cavity of NA, a few best scored fragment compounds were selected to link with Zanamivir, one NA-targeting drug. The resultant new ligands may bind both the active site and the 150-cavity of NA simultaneously. Extensive molecular dynamics simulations in explicit solvent were applied to validate the binding between NA and the designed ligands. Moreover, two control systems, a positive control using Zanamivir and a negative control using a low-affinity ligand 3-(p-tolyl) allyl-Neu5Ac2en (ETT, abbreviation reported in the PDB) found in a recent experimental work, were employed to calibrate the simulation method. During the simulations, ETT was observed to detach from NA, on the contrary, both Zanamivir and our designed ligand bind NA firmly. Our study provides a prospective way to design novel inhibitors for controlling the spread of influenza virus.
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Synthesis of Three-dimensional Polymer Nanostructures via Chemical Vapor Deposition
NASA Astrophysics Data System (ADS)
Cheng, Kenneth
Chemical vapor deposition (CVD) is a widely practiced methodology for preparing thin film polymer coatings, and the coatings can be applied to a broad range of materials, including three-dimensional solid structures and low-vapor pressure liquids. Reactive poly(p-xylylene) (PPX) coatings prepared by CVD can be used as a powerful tool for surface functionalization and bio-conjugation. The first portion of this dissertation serves to extend the use of CVD-based reactive PPX coatings as a surface functionalization strategy for the conjugation of biomolecules. Micro-structured PPX coatings having multiple surface reactive groups were fabricated. Multiple orthogonal click reactions were then employed to selectively immobilize galactose and mannobiose to the micro-structured polymer coatings. The presence of different types of carbohydrate enables lectins binding for examining ligands/cell receptor interactions. This dissertation also demonstrates the use of CVD-based reactive PPX coatings as intermediate layers to immobilize adenoviral vectors onto tissue scaffolds. The ability to tether adenoviral vectors on tissue scaffolds localizes the transduction near the scaffold surface and reduces acute toxicity and hepatic pathology cause by direct administration of the viral vector, providing a safe and efficient gene therapy delivery strategy. In the second portion of this dissertation, we explore the CVD of PPX onto surfaces coated with a thin layer of liquid crystal (LC). Instead of forming a conformal PPX coating encapsulating the LC layer, PPX assembled into an array of high-aspect ratio nanofibers inside the LC layer. The LC layer was demonstrated to act as a template where the anisotropic internal ordering of the LC facilitated the formation of nanofibers. The diameter of the nanofibers was in the range of 100 nm and could be tuned by type of LC template used, and the length of the nanofibers could be precisely controlled by varying the thickness of the LC film. The overall shape of the nanofibers could be controlled by the internal ordering of the LC template, as exemplified by the assembly of helical nanofibers using cholesteric LC as the template. PPX nanofibers could be applied to a broad range of materials, such as curved surface, metal meshes and microparticles. We successfully created nanofibers with different surface functionalities and utilized them to capture molecules of interest. We also demonstrated the synthesis of twisted nanofibers using chiral-substituted precursors. The direction and the degree of twisting of nanofibers could be controlled by the handedness and the enantiomeric excess of the chiral precursor. Finally, we showed that the LC-templated CVD method could be extended to fabricating nanofibers made of other CVD-based polymer systems, such as poly(lutidine) and poly(p-phenylene vinylene). Our work opens a new platform for designing functional polymer nanostructures with programmable geometry, alignment and chemistry. The polymer nanostructures can be attractive for applications ranging from sensors, affinity filtration, and catalytic supports.
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Graf, Neil J.
2013-01-01
Two different fabrication methods were employed to fabricate micropumps with different cross-sectional channel geometries. The first was to fabricate rectangular cross-sectional microchannel geometries using the well known fabrication method of replica molding (REM).1 The second, and far less utilized fabrication technique, was to create microchannel molds using an in-house fabricated handheld micro injection molding apparatus. The injection mold apparatus was designed for use with elastomeric room temperature vulcanization (RTV) polymers, as opposed to most other injection molding machines, which are designed for use with thermoplastic polymers. The injection mold’s bottom plate was used as a microchannel molding template. The molding template was created by threading a small-diameter wire (150 μm or less) through the injection mold’s bottom plate, with subsequent adhesion and smoothing of a thin piece of aluminum foil over the wire-raised injection mold template. When molded against, the template produced a rounded/Gaussian-shaped PDMS microchannel. The design of the injection mold will be presented, along with a direct comparison for micropump performance metrics such as flow rate, valving characteristics, and maximum backpressures attainable for each of the respective micropump channel geometries. PMID:23917263
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Hu, Ying Kai; Xie, Qian Yang; Yang, Chi; Xu, Guang Zhou
2017-01-01
Abstract The aim of this study was to introduce a novel method of mesiodens extraction using a vascularized pedicled bone flap by piezosurgery and to compare the differences between a computer-aided design surgical guide template and free-hand operation. A total of 8 patients with mesiodens, 4 with a surgical guide (group I), and 4 without it (group II) were included in the study. The surgical design was to construct a trapdoor pedicle on the superior mucoperiosteal attachment with application of piezosurgery. The bone lid was repositioned after mesiodens extraction. Group I patients underwent surgeries based on the preoperative planning with surgical guide templates, while group II patients underwent free-hand operation. The outcome variables were success rate, intraoperative time, anterior nasal spine (ANS) position, changes of nasolabial angle (NLA), and major complications. Data from the 2 groups were compared by SPSS 17.0, using Wilcoxon test. The operative time was significantly shorter in group I patients. All the mesiodentes were extracted successfully and no obvious differences of preoperative and postoperative ANS position and NLA value were found in both groups. The patients were all recovered uneventfully. Surgical guide templates can enhance clinical accuracy and reduce operative time by facilitating accurate osteotomies. PMID:28658139
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Engineering topochemical polymerizations using block copolymer templates.
Zhu, Liangliang; Tran, Helen; Beyer, Frederick L; Walck, Scott D; Li, Xin; Agren, Hans; Killops, Kato L; Campos, Luis M
2014-09-24
With the aim to achieve rapid and efficient topochemical polymerizations in the solid state, via solution-based processing of thin films, we report the integration of a diphenyldiacetylene monomer and a poly(styrene-b-acrylic acid) block copolymer template for the generation of supramolecular architectural photopolymerizable materials. This strategy takes advantage of non-covalent interactions to template a topochemical photopolymerization that yields a polydiphenyldiacetylene (PDPDA) derivative. In thin films, it was found that hierarchical self-assembly of the diacetylene monomers by microphase segregation of the block copolymer template enhances the topochemical photopolymerization, which is complete within a 20 s exposure to UV light. Moreover, UV-active cross-linkable groups were incorporated within the block copolymer template to create micropatterns of PDPDA by photolithography, in the same step as the polymerization reaction. The materials design and processing may find potential uses in the microfabrication of sensors and other important areas that benefit from solution-based processing of flexible conjugated materials.
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Lilholt, Lars; Haubro, Camilla Dremstrup; Møller, Jørn Munkhof; Aarøe, Jens; Højen, Anne Randorff; Gøeg, Kirstine Rosenbeck
2013-01-01
It is well-established that to increase acceptance of electronic clinical documentation tools, such as electronic health record (EHR) systems, it is important to have a strong relationship between those who document the clinical encounters and those who reaps the benefit of digitalized and more structured documentation. [1] Therefore, templates for EHR systems benefit from being closely related to clinical practice with a strong focus on primarily solving clinical problems. Clinical use as a driver for structured documentation has been the focus of the acute-physical-examination template (APET) development in the North Denmark Region. The template was developed through a participatory design where precision and clarity of documentation was prioritized as well as fast registration. The resulting template has approximately 700 easy accessible input possibilities and will be evaluated in clinical practice in the first quarter of 2013.
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Franzini, Raphael M.
2015-01-01
We report a new strategy for template-mediated fluorogenic chemistry that results in enhanced performance for the fluorescence detection of nucleic acids. In this approach, two successive templated reactions are required to induce a fluorescence signal, rather than only one. These novel fluorescein-labeled oligonucleotide probes, termed 2-STAR probes, contain two quencher groups tethered by separate reductively cleavable linkers. When a 2-STAR quenched probe binds adjacent to either two successive mono triphenyl-phosphine (TPP)-DNAs or a dual TPP-DNA, the two quenchers are released, resulting in a fluorescence signal. Because of the requirement for two consecutive reactions, 2-STAR probes display an unprecedented level of sequence-specificity for template-mediated probe designs. At the same time, background emission generated by off-template reactions or incomplete quenching is among the lowest of any fluorogenic reactive probes for the detection of DNA or RNA. PMID:21294182
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NASA Astrophysics Data System (ADS)
Parlett, Christopher M. A.; Isaacs, Mark A.; Beaumont, Simon K.; Bingham, Laura M.; Hondow, Nicole S.; Wilson, Karen; Lee, Adam F.
2016-02-01
The chemical functionality within porous architectures dictates their performance as heterogeneous catalysts; however, synthetic routes to control the spatial distribution of individual functions within porous solids are limited. Here we report the fabrication of spatially orthogonal bifunctional porous catalysts, through the stepwise template removal and chemical functionalization of an interconnected silica framework. Selective removal of polystyrene nanosphere templates from a lyotropic liquid crystal-templated silica sol-gel matrix, followed by extraction of the liquid crystal template, affords a hierarchical macroporous-mesoporous architecture. Decoupling of the individual template extractions allows independent functionalization of macropore and mesopore networks on the basis of chemical and/or size specificity. Spatial compartmentalization of, and directed molecular transport between, chemical functionalities affords control over the reaction sequence in catalytic cascades; herein illustrated by the Pd/Pt-catalysed oxidation of cinnamyl alcohol to cinnamic acid. We anticipate that our methodology will prompt further design of multifunctional materials comprising spatially compartmentalized functions.
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Enserch Garden Banks 388 field development template tie-back of existing subsea satellite wells
DOE Office of Scientific and Technical Information (OSTI.GOV)
Hellums, J.W.; Granhaug, O.
1995-12-31
The Flowline Jumper System (FJS) will be used by Enserch Exploration, Inc. to tie in three existing wells to the 24 well production template installed in Garden Banks Block 388. The FJS allows these existing satellite wells to be connected to the production template via standard wellbays, eliminating the need for dedicated receiver structures, or tie-in porches. Wellbays used for satellite well tie-ins are available for use as template wells following the removal of the jumper. This paper describes the considerations that led to the selection and influenced the design of the FJS. The advantages of vertical jumper systems aremore » fully discussed with respect to the GB-388 Project. A description of the major components and how they interface with the template is included to provide a better understanding of the FJS. Also included is an outline of the System Integration Testing (SIT) of the FJS.« less
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A novel chaotic stream cipher and its application to palmprint template protection
NASA Astrophysics Data System (ADS)
Li, Heng-Jian; Zhang, Jia-Shu
2010-04-01
Based on a coupled nonlinear dynamic filter (NDF), a novel chaotic stream cipher is presented in this paper and employed to protect palmprint templates. The chaotic pseudorandom bit generator (PRBG) based on a coupled NDF, which is constructed in an inverse flow, can generate multiple bits at one iteration and satisfy the security requirement of cipher design. Then, the stream cipher is employed to generate cancelable competitive code palmprint biometrics for template protection. The proposed cancelable palmprint authentication system depends on two factors: the palmprint biometric and the password/token. Therefore, the system provides high-confidence and also protects the user's privacy. The experimental results of verification on the Hong Kong PolyU Palmprint Database show that the proposed approach has a large template re-issuance ability and the equal error rate can achieve 0.02%. The performance of the palmprint template protection scheme proves the good practicability and security of the proposed stream cipher.
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NASA Astrophysics Data System (ADS)
Wan, Mimi; Zhao, Wenbo; Peng, Fang; Wang, Qi; Xu, Ping; Mao, Chun; Shen, Jian
2016-08-01
A new kind of high-quality Ag/PS coaxial nanocables can be facilely synthesized by using soft/hard templates method. In order to effectively introduce Ag sources into porous polystyrene (PS) nanotubes which were trapped in porous anodic aluminum oxide (AAO) hard template, Pluronic F127 (F127) was used as guiding agent, soft template and reductant. Meanwhile, ethylene glycol solution was also used as solvent and co-reducing agent to assist in the formation of silver nanowires. The influences of concentration of F127 and reducing reaction time on the formation of Ag/PS coaxial nanocables were discussed. Results indicated that the high-quality Ag/PS coaxial nanocables can be obtained by the mixed mode of soft/hard templates under optimized conditions. This strategy is expected to be extended to design more metal/polymer coaxial nanocables for the benefit of creation of complex and functional nanoarchitectures and components.
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Sugawara, Taku; Higashiyama, Naoki; Kaneyama, Shuichi; Sumi, Masatoshi
2017-03-15
Prospective clinical trial of the screw insertion method for posterior C1-C2 fixation utilizing the patient-specific screw guide template technique. To evaluate the efficacy of this method for insertion of C1 lateral mass screws (LMS), C2 pedicle screws (PS), and C2 laminar screws (LS). Posterior C1LMS and C2PS fixation, also known as the Goel-Harms method, can achieve immediate rigid fixation and high fusion rate, but the screw insertion carries the risk of injury to neuronal and vascular structures. Dissection of venous plexus and C2 nerve root to confirm the insertion point of the C1LMS may also cause problems. We have developed an intraoperative screw guiding method using patient-specific laminar templates. Preoperative bone images of computed tomography (CT) were analyzed using three-dimensional (3D)/multiplanar imaging software to plan the trajectories of the screws. Plastic templates with screw guiding structures were created for each lamina using 3D design and printing technology. Three types of templates were made for precise multistep guidance, and all templates were specially designed to fit and lock on the lamina during the procedure. Surgery was performed using this patient-specific screw guide template system, and placement of the screws was postoperatively evaluated using CT. Twelve patients with C1-C2 instability were treated with a total of 48 screws (24 C1LMS, 20 C2PS, 4 C2LS). Intraoperatively, each template was found to exactly fit and lock on the lamina and screw insertion was completed successfully without dissection of the venous plexus and C2 nerve root. Postoperative CT showed no cortical violation by the screws, and mean deviation of the screws from the planned trajectories was 0.70 ± 0.42 mm. The multistep, patient-specific screw guide template system is useful for intraoperative screw navigation in posterior C1-C2 fixation. This simple and economical method can improve the accuracy of screw insertion, and reduce operation time and radiation exposure of posterior C1-C2 fixation surgery. 3.
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A Problem-Solving Template for Integrating Qualitative and Quantitative Physics Instruction
ERIC Educational Resources Information Center
Fink, Janice M.; Mankey, Gary J.
2010-01-01
A problem-solving template enables a methodology of instruction that integrates aspects of both sequencing and conceptual learning. It is designed to enhance critical-thinking skills when used within the framework of a learner-centered approach to teaching, where regular, thorough assessments of student learning are key components of the…
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Games for Learning: Which Template Generates Social Construction of Knowledge?
ERIC Educational Resources Information Center
Garcia, Francisco A.
2015-01-01
The purpose of this study was to discover how three person teams use game templates (trivia, role-play, or scavenger hunt) to socially construct knowledge. The researcher designed an experimental Internet-based database to facilitate teams creating each game. Teams consisted of teachers, students, hobbyist, and business owners who shared similar…
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A Conceptual Model and Assessment Template for Capacity Evaluation in Adult Guardianship
ERIC Educational Resources Information Center
Moye, Jennifer; Butz, Steven W.; Marson, Daniel C.; Wood, Erica
2007-01-01
Purpose: We develop a conceptual model and associated assessment template that is usable across state jurisdictions for evaluating the independent-living capacity of older adults in guardianship proceedings. Design and Methods: We used an iterative process in which legal provisions for guardianship and prevailing clinical practices for capacity…
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Structure of Hepatitis C Virus Polymerase in Complex with Primer-Template RNA
Murakami, Eisuke; Lam, Angela M.; Grice, Rena L.; Du, Jinfa; Sofia, Michael J.; Furman, Philip A.; Otto, Michael J.
2012-01-01
The replication of the hepatitis C viral (HCV) genome is accomplished by the NS5B RNA-dependent RNA polymerase (RdRp), for which mechanistic understanding and structure-guided drug design efforts have been hampered by its propensity to crystallize in a closed, polymerization-incompetent state. The removal of an autoinhibitory β-hairpin loop from genotype 2a HCV NS5B increases de novo RNA synthesis by >100-fold, promotes RNA binding, and facilitated the determination of the first crystallographic structures of HCV polymerase in complex with RNA primer-template pairs. These crystal structures demonstrate the structural realignment required for primer-template recognition and elongation, provide new insights into HCV RNA synthesis at the molecular level, and may prove useful in the structure-based design of novel antiviral compounds. Additionally, our approach for obtaining the RNA primer-template-bound structure of HCV polymerase may be generally applicable to solving RNA-bound complexes for other viral RdRps that contain similar regulatory β-hairpin loops, including bovine viral diarrhea virus, dengue virus, and West Nile virus. PMID:22496223
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A faculty development workshop in narrative-based reflective writing.
Boudreau, J Donald; Liben, Stephen; Fuks, Abraham
2012-08-01
Narrative approaches are used increasingly in the health professions with a range of objectives. We must acquaint educators with this burgeoning field and prepare them for the incorporation of story-telling in their pedagogical practices. The authors describe a template for a faculty development workshop designed to foster self-reflection through the use of narrative techniques and prepare clinical teachers to deploy such approaches. The design is based on a six-year experience in delivering introductory workshops in narrative approaches to medical teachers. The workshops, which served as a model for the template, have been offered to a total of 92 clinicians being trained to mentor medical students. A generic template is described. It includes a table of core concepts from narrative theory, a set of probing questions useful in a basic technical analysis of texts and a list of initiating prompts for exercises in reflective writing. A workshop organized and deployed using this template is deliverable over a half-day. The model has proven to be feasible and highly valued by participants. It can be adapted for other contexts by educators across the continuum of health professional education.
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Rapid prototyping of microchannels with surface patterns for fabrication of polymer fibers
Goodrich, Payton J.; Sharifi, Farrokh; Hashemi, Nastaran
2015-08-14
Microfluidic technology has provided innovative solutions to numerous problems, but the cost of designing and fabricating microfluidic channels is impeding its expansion. In this study, Shrinky-Dink thermoplastic sheets are used to create multilayered complex templates for microfluidic channels. We also used inkjet and laserjet printers to raise a predetermined microchannel geometry by depositing several layers of ink for each feature consecutively. We achieved feature heights over 100 μm, which were measured and compared with surface profilometry. Templates closest to the target geometry were then used to create microfluidic devices from soft-lithography with the molds as a template. These microfluidic devicesmore » were, futhermore used to fabricate polymer microfibers using the microfluidic focusing approach to demonstrate the potential that this process has for microfluidic applications. Finally, an economic analysis was conducted to compare the price of common microfluidic template manufacturing methods. We showed that multilayer microchannels can be created significantly quicker and cheaper than current methods for design prototyping and point-of-care applications in the biomedical area.« less
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Titanium template for scaphoid reconstruction.
Haefeli, M; Schaefer, D J; Schumacher, R; Müller-Gerbl, M; Honigmann, P
2015-06-01
Reconstruction of a non-united scaphoid with a humpback deformity involves resection of the non-union followed by bone grafting and fixation of the fragments. Intraoperative control of the reconstruction is difficult owing to the complex three-dimensional shape of the scaphoid and the other carpal bones overlying the scaphoid on lateral radiographs. We developed a titanium template that fits exactly to the surfaces of the proximal and distal scaphoid poles to define their position relative to each other after resection of the non-union. The templates were designed on three-dimensional computed tomography reconstructions and manufactured using selective laser melting technology. Ten conserved human wrists were used to simulate the reconstruction. The achieved precision measured as the deviation of the surface of the reconstructed scaphoid from its virtual counterpart was good in five cases (maximal difference 1.5 mm), moderate in one case (maximal difference 3 mm) and inadequate in four cases (difference more than 3 mm). The main problems were attributed to the template design and can be avoided by improved pre-operative planning, as shown in a clinical case. © The Author(s) 2014.
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Guo, Zuojun; Li, Bo; Cheng, Li-Tien; Zhou, Shenggao; McCammon, J Andrew; Che, Jianwei
2015-02-10
Protein–ligand binding is a key biological process at the molecular level. The identification and characterization of small-molecule binding sites on therapeutically relevant proteins have tremendous implications for target evaluation and rational drug design. In this work, we used the recently developed level-set variational implicit-solvent model (VISM) with the Coulomb field approximation (CFA) to locate and characterize potential protein–small-molecule binding sites. We applied our method to a data set of 515 protein–ligand complexes and found that 96.9% of the cocrystallized ligands bind to the VISM-CFA-identified pockets and that 71.8% of the identified pockets are occupied by cocrystallized ligands. For 228 tight-binding protein–ligand complexes (i.e, complexes with experimental pKd values larger than 6), 99.1% of the cocrystallized ligands are in the VISM-CFA-identified pockets. In addition, it was found that the ligand binding orientations are consistent with the hydrophilic and hydrophobic descriptions provided by VISM. Quantitative characterization of binding pockets with topological and physicochemical parameters was used to assess the “ligandability” of the pockets. The results illustrate the key interactions between ligands and receptors and can be very informative for rational drug design.
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The application of quantum mechanics in structure-based drug design.
Mucs, Daniel; Bryce, Richard A
2013-03-01
Computational chemistry has become an established and valuable component in structure-based drug design. However the chemical complexity of many ligands and active sites challenges the accuracy of the empirical potentials commonly used to describe these systems. Consequently, there is a growing interest in utilizing electronic structure methods for addressing problems in protein-ligand recognition. In this review, the authors discuss recent progress in the development and application of quantum chemical approaches to modeling protein-ligand interactions. The authors specifically consider the development of quantum mechanics (QM) approaches for studying large molecular systems pertinent to biology, focusing on protein-ligand docking, protein-ligand binding affinities and ligand strain on binding. Although computation of binding energies remains a challenging and evolving area, current QM methods can underpin improved docking approaches and offer detailed insights into ligand strain and into the nature and relative strengths of complex active site interactions. The authors envisage that QM will become an increasingly routine and valued tool of the computational medicinal chemist.
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Waszkowycz, B; Clark, D E; Frenkel, D; Li, J; Murray, C W; Robson, B; Westhead, D R
1994-11-11
A computational approach for molecular design, PRO_LIGAND, has been developed within the PROMETHEUS molecular design and simulation system in order to provide a unified framework for the de novo generation of diverse molecules which are either similar or complementary to a specified target. In this instance, the target is a pharmacophore derived from a series of active structures either by a novel interpretation of molecular field analysis data or by a pharmacophore-mapping procedure based on clique detection. After a brief introduction to PRO_LIGAND, a detailed description is given of the two pharmacophore generation procedures and their abilities are demonstrated by the elucidation of pharmacophores for steroid binding and ACE inhibition, respectively. As a further indication of its efficacy in aiding the rational drug design process, PRO_LIGAND is then employed to build novel organic molecules to satisfy the physicochemical constraints implied by the pharmacophores.
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Structural Basis for Hormone Recognition by the Human CRFR2[alpha] G Protein-coupled Receptor
DOE Office of Scientific and Technical Information (OSTI.GOV)
Pal, Kuntal; Swaminathan, Kunchithapadam; Xu, H. Eric
2012-05-09
The mammalian corticotropin releasing factor (CRF)/urocortin (Ucn) peptide hormones include four structurally similar peptides, CRF, Ucn1, Ucn2, and Ucn3, that regulate stress responses, metabolism, and cardiovascular function by activating either of two related class B G protein-coupled receptors, CRFR1 and CRFR2. CRF and Ucn1 activate both receptors, whereas Ucn2 and Ucn3 are CRFR2-selective. The molecular basis for selectivity is unclear. Here, we show that the purified N-terminal extracellular domains (ECDs) of human CRFR1 and the CRFR2{alpha} isoform are sufficient to discriminate the peptides, and we present three crystal structures of the CRFR2{alpha} ECD bound to each of the Ucn peptides.more » The CRFR2{alpha} ECD forms the same fold observed for the CRFR1 and mouse CRFR2{beta} ECDs but contains a unique N-terminal {alpha}-helix formed by its pseudo signal peptide. The CRFR2{alpha} ECD peptide-binding site architecture is similar to that of CRFR1, and binding of the {alpha}-helical Ucn peptides closely resembles CRF binding to CRFR1. Comparing the electrostatic surface potentials of the ECDs suggests a charge compatibility mechanism for ligand discrimination involving a single amino acid difference in the receptors (CRFR1 Glu104/CRFR2{alpha} Pro-100) at a site proximate to peptide residue 35 (Arg in CRF/Ucn1, Ala in Ucn2/3). CRFR1 Glu-104 acts as a selectivity filter preventing Ucn2/3 binding because the nonpolar Ala-35 is incompatible with the negatively charged Glu-104. The structures explain the mechanisms of ligand recognition and discrimination and provide a molecular template for the rational design of therapeutic agents selectively targeting these receptors.« less
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Hevener, Kirk E.; Mehboob, Shahila; Su, Pin-Chih; Truong, Kent; Boci, Teuta; Deng, Jiangping; Ghassemi, Mahmood; Cook, James L.; Johnson, Michael E.
2011-01-01
Enoyl-acyl carrier protein (ACP) reductase, FabI, is a key enzyme in the bacterial fatty acid biosynthesis pathway (FAS II). FabI is an NADH-dependent oxidoreductase that acts to reduce enoyl-ACP substrates in a final step of the pathway. The absence of this enzyme in humans makes it an attractive target for the development of new antibacterial agents. FabI is known to be unresponsive to structure-based design efforts due to a high degree of induced fit and a mobile flexible loop encompassing the active site. Here we discuss the development, validation, and careful application of a ligand-based virtual screen used for the identification of novel inhibitors of the Francisella tularensis FabI target. In this study, four known classes of FabI inhibitors were used as templates for virtual screens that involved molecular shape and electrostatic matching. The program ROCS was used to search a high-throughput screening library for compounds that matched any of the four molecular shape queries. Matching compounds were further refined using the program EON, which compares and scores compounds by matching electrostatic properties. Using these techniques, 50 compounds were selected, ordered, and tested. The tested compounds possessed novel chemical scaffolds when compared to the input query compounds. Several hits with low micromolar activity were identified and follow-up scaffold-based searches resulted in the identification of a lead series with sub-micromolar enzyme inhibition, high ligand efficiency, and a novel scaffold. Additionally, one of the most active compounds showed promising whole-cell antibacterial activity against several Gram-positive and Gram-negative species, including the target pathogen. The results of a preliminary structure-activity relationship analysis are presented. PMID:22098466
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Rangnoi, Kuntalee; Choowongkomon, Kiattawee; O'Kennedy, Richard; Rüker, Florian; Yamabhai, Montarop
2018-06-06
A human antiaflatoxin B1 (AFB1) scFv antibody (yAFB1-c3), selected from a naı̈ve human phage-displayed scFv library, was used as a template for improving and analysis of antibody-ligand interactions using the chain-shuffling technique. The variable-heavy and variable-light (VH/VL)-shuffled library was constructed from the VH of 25 preselected clones recombined with the VL of yAFB1-c3 and vice versa. Affinity selection from these libraries demonstrated that the VH domain played an important role in the binding of scFv to free AFB1. Therefore, in the next step, VH-shuffled scFv library was constructed from variable-heavy (VH) chain repertoires, amplified from the naı̈ve library, recombined with the variable-light (VL) chain of the clone yAFB1-c3. This library was then used to select a specific scFv antibody against soluble AFB1 by a standard biopanning method. Three clones that showed improved binding properties were isolated. Amino acid sequence analysis indicated that the improved clones have amino acid mutations in framework 1 (FR1) and the complementarity determining region (CDR1) of the VH chain. One clone, designated sAFH-3e3, showed 7.5-fold improvement in sensitivity over the original scFv clone and was selected for molecular binding studies with AFB1. Homology modeling and molecular docking were used to compare the binding of this and the original clones. The results confirmed that VH is more important than VL for AFB1 binding.
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Armen, Roger S; Schiller, Stefan M; Brooks, Charles L
2010-06-01
Orthogonal aminoacyl-tRNA synthetase/tRNA pairs from archaea have been evolved to facilitate site specific in vivo incorporation of unnatural amino acids into proteins in Escherichia coli. Using this approach, unnatural amino acids have been successfully incorporated with high translational efficiency and fidelity. In this study, CHARMM-based molecular docking and free energy calculations were used to evaluate rational design of specific protein-ligand interactions for aminoacyl-tRNA synthetases. A series of novel unnatural amino acid ligands were docked into the p-benzoyl-L-phenylalanine tRNA synthetase, which revealed that the binding pocket of the enzyme does not provide sufficient space for significantly larger ligands. Specific binding site residues were mutated to alanine to create additional space to accommodate larger target ligands, and then mutations were introduced to improve binding free energy. This approach was used to redesign binding sites for several different target ligands, which were then tested against the standard 20 amino acids to verify target specificity. Only the synthetase designed to bind Man-alpha-O-Tyr was predicted to be sufficiently selective for the target ligand and also thermodynamically stable. Our study suggests that extensive redesign of the tRNA synthatase binding pocket for large bulky ligands may be quite thermodynamically unfavorable.
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Modeling G Protein-Coupled Receptors: a Concrete Possibility
Costanzi, Stefano
2010-01-01
G protein-coupled receptors (GPCRs) are a large superfamily of membrane bound signaling proteins that are involved in the regulation of a wide range of physiological functions and constitute the most common target for therapeutic intervention. Due to the paucity of crystal structures, homology modeling has become a widespread technique for the construction of GPCR models, which have been applied to the study of their structure-function relationships and to the identification of lead ligands through virtual screening. Rhodopsin has been for years the only available template. However, recent breakthroughs in GPCR crystallography have led to the solution of the structures of a few additional receptors. In light of these newly elucidated crystal structures, we have been able to produce a substantial amount of data to demonstrate that accurate models of GPCRs in complex with their ligands can be constructed through homology modeling followed by fully flexible molecular docking. These results have been confirmed by our success in the first blind assessment of GPCR modeling and docking, organized in coordination with the solution of the X-ray structure of the adenosine A2A receptor. Taken together, these data indicate that: a) the transmembrane helical bundle can be modeled with considerable accuracy; b) predicting the binding mode of a ligand, although doable, is challenging; c) modeling of the extracellular and intracellular loops is still problematic. PMID:21253444
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Determination of mutated genes in the presence of wild-type DNA by using molecular beacons as probe
NASA Astrophysics Data System (ADS)
Zhang, Yonghua; Ai, Junjie; Gu, Qiaorong; Gao, Qiang; Qi, Honglan; Zhang, Chengxiao
2017-03-01
Low-abundance mutations in the presence of wild-type DNA can be determined using molecular beacon (MB) as probe. A MB is generally used as DNA probe because it can distinguish single-base mismatched target DNA from fully matched target DNA. However, the probe can not determine low-abundance mutations in the presence of wild-type DNA. In this study, this limitation is addressed by enhancing the stability of unpaired base-containing dsDNA with a hydrogen-bonding ligand, which was added after hybridization of the MB to the target DNA. The ligand formed hydrogen bonds with unpaired bases and stabilized the unpaired base-containing dsDNA if target DNA is mutated one. As a result, more MBs were opened by the mutant genes in the presence of the ligand and a further increase in the fluorescence intensity was obtained. By contrast, fluorescence intensity did not change if target DNA is wild-type one. Consequent increase in the fluorescence intensity of the MB was regarded as a signal derived from mutant genes. The proposed method was applied in synthetic template systems to determine point mutation in DNA obtained from PCR analysis. The method also allows rapid and simple discrimination of a signal if it is originated in the presence of mutant gene or alternatively by a lower concentration of wild gene.
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Rational and Modular Design of Potent Ligands Targeting the RNA that Causes Myotonic Dystrophy 2
Lee, Melissa M.; Pushechnikov, Alexei; Disney, Matthew D.
2009-01-01
Most ligands targeting RNA are identified through screening a therapeutic target for binding members of a ligand library. A potential alternative way to construct RNA binders is through rational design using information about the RNA motifs ligands prefer to bind. Herein, we describe such an approach to design modularly assembled ligands targeting the RNA that causes myotonic dystrophy type 2 (DM2), a currently untreatable disease. A previous study identified that 6′-N-5-hexynoate kanamycin A (1) prefers to bind 2×2 nucleotide, pyrimidine-rich RNA internal loops. Multiple copies of such loops were found in the RNA hairpin that causes DM2. The 1 ligand was then modularly displayed on a peptoid scaffold with varied number and spacing to target several internal loops simultaneously. Modularly assembled ligands were tested for binding to a series of RNAs and for inhibiting the formation of the toxic DM2 RNA-muscleblind protein (MBNL-1) interaction. The most potent ligand displays three 1 modules, each separated by four spacing submonomers, and inhibits the formation of the RNA-protein complex with an IC50 of 25 nM. This ligand is higher affinity and more specific for binding DM2 RNA than MBNL-1. It binds the DM2 RNA at least 20-times more tightly than related RNAs and 15-fold more tightly than MBNL-1. A related control peptoid displaying 6′-N-5-hexynoate neamine (2) is >100-fold less potent at inhibiting the RNA-protein interaction and binds to DM2 RNA >125-fold more weakly. Uptake studies into a mouse myoblast cell line also show that the most potent ligand is cell permeable. PMID:19348464
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GREEN: A program package for docking studies in rational drug design
NASA Astrophysics Data System (ADS)
Tomioka, Nobuo; Itai, Akiko
1994-08-01
A program package, GREEN, has been developed that enables docking studies between ligand molecules and a protein molecule. Based on the structure of the protein molecule, the physical and chemical environment of the ligand-binding site is expressed as three-dimensional grid-point data. The grid-point data are used for the real-time evaluation of the protein-ligand interaction energy, as well as for the graphical representation of the binding-site environment. The interactive docking operation is facilitated by various built-in functions, such as energy minimization, energy contribution analysis and logging of the manipulation trajectory. Interactive modeling functions are incorporated for designing new ligand molecules while considering the binding-site environment and the protein-ligand interaction. As an example of the application of GREEN, a docking study is presented on the complex between trypsin and a synthetic trypsin inhibitor. The program package will be useful for rational drug design, based on the 3D structure of the target protein.
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Design and synthesis of binucleating macrocyclic clefts derived from Schiff-base calixpyrroles.
Givaja, Gonzalo; Volpe, Manuel; Leeland, James W; Edwards, Michael A; Young, Thomas K; Darby, S Barnie; Reid, Stuart D; Blake, Alexander J; Wilson, Claire; Wolowska, Joanna; McInnes, Eric J L; Schröder, Martin; Love, Jason B
2007-01-01
The syntheses, characterisation and complexation reactions of a series of binucleating Schiff-base calixpyrrole macrocycles are described. The acid-templated [2+2] condensations between meso-disubstituted diformyldipyrromethanes and o-phenylenediamines generate the Schiff-base pyrrolic macrocycles H(4)L(1) to H(4)L(6) upon basic workup. The single-crystal X-ray structures of both H(4)L(3).2 EtOH and H(4)L(6).H2O confirm that [2+2] cyclisation has occurred, with either EtOH or H2O hydrogen-bonded within the macrocyclic cleft. A series of complexation reactions generate the dipalladium [Pd2(L)] (L=L(1) to L(5)), dinickel [Ni2(L(1))] and dicopper [Cu2(L)] (L=L(1) to L(3)) complexes. All of these complexes have been structurally characterised in the solid state and are found to adopt wedged structures that are enforced by the rigidity of the aryl backbone to give a cleft reminiscent of the structures of Pacman porphyrins. The binuclear nickel complexes [Ni2(mu-OMe)2Cl2(HOMe)2(H(4)L(1))] and [Ni2(mu-OH)2Cl2(HOMe)(H(4)L(5))] have also been prepared, although in these cases the solid-state structures show that the macrocyclic ligand remains protonated at the pyrrolic nitrogen atoms, and the Ni(II) cations are therefore co-ordinated by the imine nitrogen atoms only to give an open conformation for the complex. The dicopper complex [Cu2(L(3))] was crystallised in the presence of pyridine to form the adduct [Cu2(py)(L(3))], in which, in the solid state, the pyridine ligand is bound within the binuclear molecular cleft. Reaction between H(4)L(1) and [Mn(thf){N(SiMe(3))2}2] results in clean formation of the dimanganese complex [Mn2(L(1))], which, upon crystallisation, formed the mixed-valent complex [Mn2(mu-OH)(L(1))] in which the hydroxo ligand bridges the metal centres within the molecular cleft.
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Architecture effects on multivalent interactions by polypeptide-based multivalent ligands
NASA Astrophysics Data System (ADS)
Liu, Shuang
Multivalent interactions are characterized by the simultaneous binding between multiple ligands and multiple binding sites, either in solutions or at interfaces. In biological systems, most multivalent interactions occur between protein receptors and carbohydrate ligands through hydrogen-bonding and hydrophobic interactions. Compared with weak affinity binding between one ligand and one binding site, i.e. monovalent interaction, multivalent interactioins provide greater avidity and specificity, and therefore play unique roles in a broad range of biological activities. Moreover, the studies of multivalent interactions are also essential for producing effective inhibitors and effectors of biological processes that could have important therapeutic applications. Synthetic multivalent ligands have been designed to mimic the biological functions of natural multivalent interactions, and various types of scaffolds have been used to display multiple ligands, including small molecules, linear polymers, dendrimers, nanoparticle surfaces, monolayer surfaces and liposomes. Studies have shown that multivalent interactions can be highly affected by various architectural parameters of these multivalent ligands, including ligand identities, valencies, spacing, ligand densities, nature of linker arms, scaffold length and scaffold conformation. Most of these multivalent ligands are chemically synthesized and have limitations of controlling over sequence and conformation, which is a barrier for mimicking ordered and controlled natural biological systems. Therefore, multivalent ligands with precisely controlled architecture are required for improved structure-function relationship studies. Protein engineering methods with subsequent chemical coupling of ligands provide significant advantages of controlling over backbone conformation and functional group placement, and therefore have been used to synthesize recombinant protein-based materials with desired properties similar to natural protein materials, including structural as well as functional proteins. Therefore, polypeptide-based multivalent scaffolds are used to display ligands to assess the contribution of different architectural parameters to the multivalent binding events. In this work, a family of alanine-rich alpha-helical glycopolypeptides was designed and synthesized by a combination of protein engineering and chemical coupling, to display two types of saccharide ligands for two different multivalent binding systems. The valencies, chain length and spacing between adjacent ligands of these multivalent ligands were designed in order to study architecture effects on multivalent interactions. The polypeptides and their glycoconjugates were characterized via various methods, including SDS-PAGE, NMR, HPLC, amino acid analysis (AAA), MALDI, circular dichroism (CD) and GPC. In the first multivalent binding system, cholera toxin B pentamer (CT B5) was chosen to be the protein receptor due to its well-characterized structure, lack of significant steric interference of binding to multiple binding sites, and requirement of only simple monosaccharide as ligands. Galactopyranoside was incorporated into polypeptide scaffolds through amine-carboxylic acid coupling to the side chains of glutamic acid residues. The inhibition and binding to CT B5 of these glycopolypeptide ligands were evaluated by direct enzyme-linked assay (DELA). As a complement method, weak affinity chromatography (WAC) was also used to evaluate glycopolypeptides binding to a CT B5 immobilized column. The architecture effects on CT B 5 inhibition are discussed. In the second system, cell surface receptor L-selectin was targeted by polypeptide-based multivalent ligands containing disulfated galactopyranoside ligands, due to its important roles in various immunological activities. The effects of glycopolypeptide architectural variables L-selectin shedding were evaluated via ELISA-based assays. These polypeptide-based multivalent ligands are suggested to be useful for elucidating architecture effects on multivalent interactions, manipulating multivalent interactions and the subsequent cellular responses in different systems. These materials have great potential applications in therapeutics and could also provide guidelines for design of multivalent ligands for other protein receptors.
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Pathania, Shivalika; Randhawa, Vinay; Bagler, Ganesh
2013-01-01
Aldose Reductase (AR) is implicated in the development of secondary complications of diabetes, providing an interesting target for therapeutic intervention. Extracts of Rauvolfia serpentina, a medicinal plant endemic to the Himalayan mountain range, have been known to be effective in alleviating diabetes and its complications. In this study, we aim to prospect for novel plant-derived inhibitors from R. serpentina and to understand structural basis of their interactions. An extensive library of R. serpentina molecules was compiled and computationally screened for inhibitory action against AR. The stability of complexes, with docked leads, was verified using molecular dynamics simulations. Two structurally distinct plant-derived leads were identified as inhibitors: indobine and indobinine. Further, using these two leads as templates, 16 more leads were identified through ligand-based screening of their structural analogs, from a small molecules database. Thus, we obtained plant-derived indole alkaloids, and their structural analogs, as potential AR inhibitors from a manually curated dataset of R. serpentina molecules. Indole alkaloids reported herein, as a novel structural class unreported hitherto, may provide better insights for designing potential AR inhibitors with improved efficacy and fewer side effects. PMID:23613832
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Pathania, Shivalika; Randhawa, Vinay; Bagler, Ganesh
2013-01-01
Aldose Reductase (AR) is implicated in the development of secondary complications of diabetes, providing an interesting target for therapeutic intervention. Extracts of Rauvolfia serpentina, a medicinal plant endemic to the Himalayan mountain range, have been known to be effective in alleviating diabetes and its complications. In this study, we aim to prospect for novel plant-derived inhibitors from R. serpentina and to understand structural basis of their interactions. An extensive library of R. serpentina molecules was compiled and computationally screened for inhibitory action against AR. The stability of complexes, with docked leads, was verified using molecular dynamics simulations. Two structurally distinct plant-derived leads were identified as inhibitors: indobine and indobinine. Further, using these two leads as templates, 16 more leads were identified through ligand-based screening of their structural analogs, from a small molecules database. Thus, we obtained plant-derived indole alkaloids, and their structural analogs, as potential AR inhibitors from a manually curated dataset of R. serpentina molecules. Indole alkaloids reported herein, as a novel structural class unreported hitherto, may provide better insights for designing potential AR inhibitors with improved efficacy and fewer side effects.
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Widger, Leland R.; Siegler, Maxime A.
2013-01-01
The unsymmetrical iron(II) bis(imino)pyridine complexes [FeII(LN3SMe)(H2O)3](OTf)2 (1), and [FeII(LN3SMe)Cl2] (2) were synthesized and their reactivity with O2 was examined. Complexes 1 and 2 were characterized by single crystal X-ray crystallography, LDI-MS, 1H-NMR and elemental analysis. The LN3SMe ligand was designed to incorporate a single sulfide donor and relies on the bis(imino)pyridine scaffold. This scaffold was selected for its ease of synthesis and its well-precedented ability to stabilize Fe(II) ions. Complexes 1 and 2 ware prepared via a metal-assisted template reaction from the unsymmetrical pyridyl ketone precursor 2-(O=CMe)-6-(2,6-(iPr2-C6H3N=CMe)-C5H3N. Reaction of 1 with O2 was shown to afford the S-oxygenated sulfoxide complex [Fe(LN3S(O)Me)(OTf)]2+(3), whereas compound 2, under the same reaction conditions, afforded the corresponding sulfone complex [Fe(LN3S(O2)Me)Cl]2+ (4). PMID:23878411
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Bergeron, Zachary L.; Bingham, Jon-Paul
2012-01-01
Scorpion toxins have been central to the investigation and understanding of the physiological role of potassium (K+) channels and their expansive function in membrane biophysics. As highly specific probes, toxins have revealed a great deal about channel structure and the correlation between mutations, altered regulation and a number of human pathologies. Radio- and fluorescently-labeled toxin isoforms have contributed to localization studies of channel subtypes in expressing cells, and have been further used in competitive displacement assays for the identification of additional novel ligands for use in research and medicine. Chimeric toxins have been designed from multiple peptide scaffolds to probe channel isoform specificity, while advanced epitope chimerization has aided in the development of novel molecular therapeutics. Peptide backbone cyclization has been utilized to enhance therapeutic efficiency by augmenting serum stability and toxin half-life in vivo as a number of K+-channel isoforms have been identified with essential roles in disease states ranging from HIV, T-cell mediated autoimmune disease and hypertension to various cardiac arrhythmias and Malaria. Bioengineered scorpion toxins have been monumental to the evolution of channel science, and are now serving as templates for the development of invaluable experimental molecular therapeutics. PMID:23202307
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Copp, Stacy M; Schultz, Danielle E; Swasey, Steven; Gwinn, Elisabeth G
2015-03-24
The remarkable precision that DNA scaffolds provide for arraying nanoscale optical elements enables optical phenomena that arise from interactions of metal nanoparticles, dye molecules, and quantum dots placed at nanoscale separations. However, control of ensemble optical properties has been limited by the difficulty of achieving uniform particle sizes and shapes. Ligand-stabilized metal clusters offer a route to atomically precise arrays that combine desirable attributes of both metals and molecules. Exploiting the unique advantages of the cluster regime requires techniques to realize controlled nanoscale placement of select cluster structures. Here we show that atomically monodisperse arrays of fluorescent, DNA-stabilized silver clusters can be realized on a prototypical scaffold, a DNA nanotube, with attachment sites separated by <10 nm. Cluster attachment is mediated by designed DNA linkers that enable isolation of specific clusters prior to assembly on nanotubes and preserve cluster structure and spectral purity after assembly. The modularity of this approach generalizes to silver clusters of diverse sizes and DNA scaffolds of many types. Thus, these silver cluster nano-optical elements, which themselves have colors selected by their particular DNA templating oligomer, bring unique dimensions of control and flexibility to the rapidly expanding field of nano-optics.
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Sutherland, Tara D; Huson, Mickey G; Rapson, Trevor D
2018-01-01
Sequence-definable polymers are seen as a prerequisite for design of future materials, with many polymer scientists regarding such polymers as the holy grail of polymer science. Recombinant proteins are sequence-defined polymers. Proteins are dictated by DNA templates and therefore the sequence of amino acids in a protein is defined, and molecular biology provides tools that allow redesign of the DNA as required. Despite this advantage, proteins are underrepresented in materials science. In this publication we investigate the advantages and limitations of using proteins as templates for rational design of new materials. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.
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Structure-based design of ligands for protein basic domains: Application to the HIV-1 Tat protein
NASA Astrophysics Data System (ADS)
Filikov, Anton V.; James, Thomas L.
1998-05-01
A methodology has been developed for designing ligands to bind a flexible basic protein domain where the structure of the domain is essentially known. It is based on an empirical binding free energy function developed for highly charged complexes and on Monte Carlo simulations in internal coordinates with both the ligand and the receptor being flexible. HIV-1 encodes a transactivating regulatory protein called Tat. Binding of the basic domain of Tat to TAR RNA is required for efficient transcription of the viral genome. The structure of a biologically active peptide containing the Tat basic RNA-binding domain is available from NMR studies. The goal of the current project is to design a ligand which will bind to that basic domain and potentially inhibit the TAR-Tat interaction. The basic domain contains six arginine and two lysine residues. Our strategy was to design a ligand for arginine first and then a superligand for the basic domain by joining arginine ligands with a linker. Several possible arginine ligands were obtained by searching the Available Chemicals Directory with DOCK 3.5 software. Phytic acid, which can potentially bind multiple arginines, was chosen as a building block for the superligand. Calorimetric binding studies of several compounds to methylguanidine and Arg-/Lys-containing peptides were performed. The data were used to develop an empirical binding free energy function for prediction of affinity of the ligands for the Tat basic domain. Modeling of the conformations of the complexes with both the superligand and the basic domain being flexible has been carried out via Biased Probability Monte Carlo (BPMC) simulations in internal coordinates (ICM 2.6 suite of programs). The simulations used parameters to ensure correct folding, i.e., consistent with the experimental NMR structure of a 25-residue Tat peptide, from a random starting conformation. Superligands for the basic domain were designed by joining together two molecules of phytic acid with peptidic and peptidomimetic linkers. The linkers were refined by varying the length and side chains of the linking residues, carrying out BPMC simulations, and evaluation of the binding free energy for the best energy conformation. The dissociation constant of the best ligand designed is estimated to be in the low- to mid-nanomolar range.
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Tian, Ye; Huang, Xiaoqiang; Zhu, Yushan
2015-08-01
Enzyme amino-acid sequences at ligand-binding interfaces are evolutionarily optimized for reactions, and the natural conformation of an enzyme-ligand complex must have a low free energy relative to alternative conformations in native-like or non-native sequences. Based on this assumption, a combined energy function was developed for enzyme design and then evaluated by recapitulating native enzyme sequences at ligand-binding interfaces for 10 enzyme-ligand complexes. In this energy function, the electrostatic interaction between polar or charged atoms at buried interfaces is described by an explicitly orientation-dependent hydrogen-bonding potential and a pairwise-decomposable generalized Born model based on the general side chain in the protein design framework. The energy function is augmented with a pairwise surface-area based hydrophobic contribution for nonpolar atom burial. Using this function, on average, 78% of the amino acids at ligand-binding sites were predicted correctly in the minimum-energy sequences, whereas 84% were predicted correctly in the most-similar sequences, which were selected from the top 20 sequences for each enzyme-ligand complex. Hydrogen bonds at the enzyme-ligand binding interfaces in the 10 complexes were usually recovered with the correct geometries. The binding energies calculated using the combined energy function helped to discriminate the active sequences from a pool of alternative sequences that were generated by repeatedly solving a series of mixed-integer linear programming problems for sequence selection with increasing integer cuts.
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Manzoni, Francesco; Wallerstein, Johan; Schrader, Tobias E; Ostermann, Andreas; Coates, Leighton; Akke, Mikael; Blakeley, Matthew P; Oksanen, Esko; Logan, Derek T
2018-05-24
The medically important drug target galectin-3 binds galactose-containing moieties on glycoproteins through an intricate pattern of hydrogen bonds to a largely polar surface-exposed binding site. All successful inhibitors of galectin-3 to date have been based on mono- or disaccharide cores closely resembling natural ligands. A detailed understanding of the H-bonding networks in these natural ligands will provide an improved foundation for the design of novel inhibitors. Neutron crystallography is an ideal technique to reveal the geometry of hydrogen bonds because the positions of hydrogen atoms are directly detected rather than being inferred from the positions of heavier atoms as in X-ray crystallography. We present three neutron crystal structures of the C-terminal carbohydrate recognition domain of galectin-3: the ligand-free form and the complexes with the natural substrate lactose and with glycerol, which mimics important interactions made by lactose. The neutron crystal structures reveal unambiguously the exquisite fine-tuning of the hydrogen bonding pattern in the binding site to the natural disaccharide ligand. The ligand-free structure shows that most of these hydrogen bonds are preserved even when the polar groups of the ligand are replaced by water molecules. The protonation states of all histidine residues in the protein are also revealed and correlate well with NMR observations. The structures give a solid starting point for molecular dynamics simulations and computational estimates of ligand binding affinity that will inform future drug design.
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Zheng, Pengfei; Xu, Peng; Yao, Qingqiang; Tang, Kai; Lou, Yue
2017-01-01
To explore the feasibility of 3D-printed navigation template in proximal femoral varus rotation and shortening osteotomy for older children with developmental dysplasia of the hip (DDH). Between June 2014 and May 2015, navigation templates were designed and used for 12 DDH patients. Surgical information and outcomes were compared to 13 patients undergoing the same surgery but without navigation template. In template-guided patient group, operation time (21.08 min vs. 46.92 min), number of X-ray exposures (3.92 vs. 6.69), and occurrence of femoral epiphysis damage (0 vs. 0.92) were significantly decreased (P < 0.05). Furthermore, after 12–18 months follow-up, 66.7% and 16.7% of the hips in template-guided group were rated as excellent or good, respectively, according to the McKay criteria; 83.3% and 16.7% by using the Severin criteria respectively. By contrast, 46.2% and 23.1% of the hips in traditional operation group were classed as excellent or good, respectively, using the McKay criteria; 46.2% and 30.8% by using the Severin criteria respectively. The template-guided group achieved a better outcome; however, there was no significant difference. Application of the navigation template for older DDH children can reduce the operation time, radiation exposure, and epiphysis damage, which also simplifies surgery and improves precision. PMID:28322290
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Shedding Light on Anesthetic Mechanisms: Application of Photoaffinity Ligands
Woll, Kellie A.; Dailey, William P.; Brannigan, Grace; Eckenhoff, Roderic G.
2016-01-01
Anesthetic photoaffinity ligands have had an increasing presence within anesthesiology research. These ligands mimic parent general anesthetics, and allow investigators to study anesthetic interactions with receptors and enzymes; identify novel targets; and determine distribution within biological systems. To date nearly all general anesthetics used in medicine have a corresponding photoaffinity ligand represented in the literature. In this review we examine all aspects of the current methodologies, including ligand design, characterization and deployment. Finally we offer points of consideration and highlight the future outlook as more photoaffinity ligands emerge within the field. PMID:27464974
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Shedding Light on Anesthetic Mechanisms: Application of Photoaffinity Ligands.
Woll, Kellie A; Dailey, William P; Brannigan, Grace; Eckenhoff, Roderic G
2016-11-01
Anesthetic photoaffinity ligands have had an increasing presence within anesthesiology research. These ligands mimic parent general anesthetics and allow investigators to study anesthetic interactions with receptors and enzymes; identify novel targets; and determine distribution within biological systems. To date, nearly all general anesthetics used in medicine have a corresponding photoaffinity ligand represented in the literature. In this review, we examine all aspects of the current methodologies, including ligand design, characterization, and deployment. Finally we offer points of consideration and highlight the future outlook as more photoaffinity ligands emerge within the field.
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NASA Astrophysics Data System (ADS)
Slynko, Inna; Da Silva, Franck; Bret, Guillaume; Rognan, Didier
2016-09-01
High affinity ligands for a given target tend to share key molecular interactions with important anchoring amino acids and therefore often present quite conserved interaction patterns. This simple concept was formalized in a topological knowledge-based scoring function (GRIM) for selecting the most appropriate docking poses from previously X-rayed interaction patterns. GRIM first converts protein-ligand atomic coordinates (docking poses) into a simple 3D graph describing the corresponding interaction pattern. In a second step, proposed graphs are compared to that found from template structures in the Protein Data Bank. Last, all docking poses are rescored according to an empirical score (GRIMscore) accounting for overlap of maximum common subgraphs. Taking the opportunity of the public D3R Grand Challenge 2015, GRIM was used to rescore docking poses for 36 ligands (6 HSP90α inhibitors, 30 MAP4K4 inhibitors) prior to the release of the corresponding protein-ligand X-ray structures. When applied to the HSP90α dataset, for which many protein-ligand X-ray structures are already available, GRIM provided very high quality solutions (mean rmsd = 1.06 Å, n = 6) as top-ranked poses, and significantly outperformed a state-of-the-art scoring function. In the case of MAP4K4 inhibitors, for which preexisting 3D knowledge is scarce and chemical diversity is much larger, the accuracy of GRIM poses decays (mean rmsd = 3.18 Å, n = 30) although GRIM still outperforms an energy-based scoring function. GRIM rescoring appears to be quite robust with comparison to the other approaches competing for the same challenge (42 submissions for the HSP90 dataset, 27 for the MAP4K4 dataset) as it ranked 3rd and 2nd respectively, for the two investigated datasets. The rescoring method is quite simple to implement, independent on a docking engine, and applicable to any target for which at least one holo X-ray structure is available.
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Johnson, David K.; Karanicolas, John
2016-01-01
Protein-protein interactions play important roles in virtually all cellular processes, making them enticing targets for modulation by small-molecule therapeutics: specific examples have been well validated in diseases ranging from cancer and autoimmune disorders, to bacterial and viral infections. Despite several notable successes, however, overall these remain a very challenging target class. Protein interaction sites are especially challenging for computational approaches, because the target protein surface often undergoes a conformational change to enable ligand binding: this confounds traditional approaches for virtual screening. Through previous studies, we demonstrated that biased “pocket optimization” simulations could be used to build collections of low-energy pocket-containing conformations, starting from an unbound protein structure. Here, we demonstrate that these pockets can further be used to identify ligands that complement the protein surface. To do so, we first build from a given pocket its “exemplar”: a perfect, but non-physical, pseudo-ligand that would optimally match the shape and chemical features of the pocket. In our previous studies, we used these exemplars to quantitatively compare protein surface pockets to one another. Here, we now introduce this exemplar as a template for pharmacophore-based screening of chemical libraries. Through a series of benchmark experiments, we demonstrate that this approach exhibits comparable performance as traditional docking methods for identifying known inhibitors acting at protein interaction sites. However, because this approach is predicated on ligand/exemplar overlays, and thus does not require explicit calculation of protein-ligand interactions, exemplar screening provides a tremendous speed advantage over docking: 6 million compounds can be screened in about 15 minutes on a single 16-core, dual-GPU computer. The extreme speed at which large compound libraries can be traversed easily enables screening against a “pocket-optimized” ensemble of protein conformations, which in turn facilitates identification of more diverse classes of active compounds for a given protein target. PMID:26726827
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NASA Astrophysics Data System (ADS)
Castro-Lopez, Rafael; Fernandez, Francisco V.; Rodriguez Vazquez, Angel
2005-06-01
Accelerating the synthesis of increasingly complex analog integrated circuits is key to bridge the widening gap between what we can integrate and what we can design while meeting ever-tightening time-to-market constraints. It is a well-known fact in the semiconductor industry that such goal can only be attained by means of adequate CAD methodologies, techniques, and accompanying tools. This is particularly important in analog physical synthesis (a.k.a. layout generation), where large sensitivities of the circuit performances to the many subtle details of layout implementation (device matching, loading and coupling effects, reliability, and area features are of utmost importance to analog designers), render complete automation a truly challenging task. To approach the problem, two directions have been traditionally considered, knowledge-based and optimization-based, both with their own pros and cons. Besides, recently reported solutions oriented to speed up the overall design flow by means of reuse-based practices or by cutting off time-consuming, error-prone spins between electrical and layout synthesis (a technique known as layout-aware synthesis), rely on a outstandingly rapid yet efficient layout generation method. This paper analyses the suitability of procedural layout generation based on templates (a knowledge-based approach) by examining the requirements that both layout reuse and layout-aware solutions impose, and how layout templates face them. The ability to capture the know-how of experienced layout designers and the turnaround times for layout instancing are considered main comparative aspects in relation to other layout generation approaches. A discussion on the benefit-cost trade-off of using layout templates is also included. In addition to this analysis, the paper delves deeper into systematic techniques to develop fully reusable layout templates for analog circuits, either for a change of the circuit sizing (i.e., layout retargeting) or a change of the fabrication process (i.e., layout migration). Several examples implemented with the Cadence's Virtuoso tool suite are provided as demonstration of the paper's contributions.
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Anion Exchange in II-VI Semiconducting Nanostructures via Atomic Templating.
Agarwal, Rahul; Krook, Nadia M; Ren, Ming-Liang; Tan, Liang Z; Liu, Wenjing; Rappe, Andrew M; Agarwal, Ritesh
2018-03-14
Controlled chemical transformation of nanostructures is a promising technique to obtain precisely designed novel materials, which are difficult to synthesize otherwise. We report high-temperature vapor-phase anion-exchange reactions to chemically transform II-VI semiconductor nanostructures (100-300 nm length scale) while retaining the single crystallinity, crystal structure, morphology, and even defect distribution of the parent material via atomic templating. The concept of atomic templating is employed to obtain kinetically controlled, thermodynamically metastable structural phases such as zincblende CdSe and CdS from zincblende CdTe upon complete chemical replacement of Te with Se or S. The underlying transformation mechanisms are explained through first-principles density functional theory calculations. Atomic templating is a unique path to independently tune materials' phase and composition at the nanoscale, allowing the synthesis of novel materials.
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A Hybrid Approach to Protect Palmprint Templates
Sun, Dongmei; Xiong, Ke; Qiu, Zhengding
2014-01-01
Biometric template protection is indispensable to protect personal privacy in large-scale deployment of biometric systems. Accuracy, changeability, and security are three critical requirements for template protection algorithms. However, existing template protection algorithms cannot satisfy all these requirements well. In this paper, we propose a hybrid approach that combines random projection and fuzzy vault to improve the performances at these three points. Heterogeneous space is designed for combining random projection and fuzzy vault properly in the hybrid scheme. New chaff point generation method is also proposed to enhance the security of the heterogeneous vault. Theoretical analyses of proposed hybrid approach in terms of accuracy, changeability, and security are given in this paper. Palmprint database based experimental results well support the theoretical analyses and demonstrate the effectiveness of proposed hybrid approach. PMID:24982977
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A hybrid approach to protect palmprint templates.
Liu, Hailun; Sun, Dongmei; Xiong, Ke; Qiu, Zhengding
2014-01-01
Biometric template protection is indispensable to protect personal privacy in large-scale deployment of biometric systems. Accuracy, changeability, and security are three critical requirements for template protection algorithms. However, existing template protection algorithms cannot satisfy all these requirements well. In this paper, we propose a hybrid approach that combines random projection and fuzzy vault to improve the performances at these three points. Heterogeneous space is designed for combining random projection and fuzzy vault properly in the hybrid scheme. New chaff point generation method is also proposed to enhance the security of the heterogeneous vault. Theoretical analyses of proposed hybrid approach in terms of accuracy, changeability, and security are given in this paper. Palmprint database based experimental results well support the theoretical analyses and demonstrate the effectiveness of proposed hybrid approach.
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Matching organic libraries with protein-substructures
NASA Astrophysics Data System (ADS)
Preissner, R.; Goede, A.; Rother, K.; Osterkamp, F.; Koert, U.; Froemmel, C.
2001-09-01
We present a general approach which allows automatic identification of sub-structures in proteins that resemble given three-dimensional templates. This paper documents its success with non-peptide templates such as β-turn mimetics. We considered well-tested turn-mimetics such as the bicyclic turned dipeptide (BTD), spiro lactam (Spiro) and the 2,5-disubstituded tetrahydrofuran (THF), a new furan-derivative which was recently developed and characterized. The detected geometric similarity between the templates and the protein patches corresponds to r.m.s.-values of 0.3 Å for more than 80% of the constituting atoms, which is typical for active site comparisons of homologous proteins. This fast automatic procedure might be of biomedical value for finding special mimicking leads for particular protein sub-structures as well as for template-assembled synthetic protein (TASP) design.
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A Quantitative Measure of Conformational Changes in Apo, Holo and Ligand-Bound Forms of Enzymes.
Singh, Satendra; Singh, Atul Kumar; Wadhwa, Gulshan; Singh, Dev Bukhsh; Dwivedi, Seema; Gautam, Budhayash; Ramteke, Pramod W
2016-06-01
Determination of the native geometry of the enzymes and ligand complexes is a key step in the process of structure-based drug designing. Enzymes and ligands show flexibility in structural behavior as they come in contact with each other. When ligand binds with active site of the enzyme, in the presence of cofactor some structural changes are expected to occur in the active site. Motivation behind this study is to determine the nature of conformational changes as well as regions where such changes are more pronounced. To measure the structural changes due to cofactor and ligand complex, enzyme in apo, holo and ligand-bound forms is selected. Enzyme data set was retrieved from protein data bank. Fifteen triplet groups were selected for the analysis of structural changes based on selection criteria. Structural features for selected enzymes were compared at the global as well as local region. Accessible surface area for the enzymes in entire triplet set was calculated, which describes the change in accessible surface area upon binding of cofactor and ligand with the enzyme. It was observed that some structural changes take place during binding of ligand in the presence of cofactor. This study will helps in understanding the level of flexibility in protein-ligand interaction for computer-aided drug designing.
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Crystallization of bi-functional ligand protein complexes.
Antoni, Claudia; Vera, Laura; Devel, Laurent; Catalani, Maria Pia; Czarny, Bertrand; Cassar-Lajeunesse, Evelyn; Nuti, Elisa; Rossello, Armando; Dive, Vincent; Stura, Enrico Adriano
2013-06-01
Homodimerization is important in signal transduction and can play a crucial role in many other biological systems. To obtaining structural information for the design of molecules able to control the signalization pathways, the proteins involved will have to be crystallized in complex with ligands that induce dimerization. Bi-functional drugs have been generated by linking two ligands together chemically and the relative crystallizability of complexes with mono-functional and bi-functional ligands has been evaluated. There are problems associated with crystallization with such ligands, but overall, the advantages appear to be greater than the drawbacks. The study involves two matrix metalloproteinases, MMP-12 and MMP-9. Using flexible and rigid linkers we show that it is possible to control the crystal packing and that by changing the ligand-enzyme stoichiometric ratio, one can toggle between having one bi-functional ligand binding to two enzymes and having the same ligand bound to each enzyme. The nature of linker and its point of attachment on the ligand can be varied to aid crystallization, and such variations can also provide valuable structural information about the interactions made by the linker with the protein. We report here the crystallization and structure determination of seven ligand-dimerized complexes. These results suggest that the use of bi-functional drugs can be extended beyond the realm of protein dimerization to include all drug design projects. Copyright © 2013 Elsevier Inc. All rights reserved.
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Müllner, Markus; Cui, Jiwei; Noi, Ka Fung; Gunawan, Sylvia T; Caruso, Frank
2014-06-03
We report a templating approach for the preparation of functional polymer replica particles via surface-initiated polymerization in mesoporous silica templates. Subsequent removal of the template resulted in discrete polymer particles. Furthermore, redox-responsive replica particles could be engineered to disassemble in a reducing environment. Particles, made of poly(methacryloyloxyethyl phosphorylcholine) (PMPC) or poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA), exhibited very low association to human cancer cells (below 5%), which renders the reported charge-neutral polymer particles a modular and versatile class of highly functional carriers with potential applications in drug delivery.
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Ghedira, Rim; Papazova, Nina; Vuylsteke, Marnik; Ruttink, Tom; Taverniers, Isabel; De Loose, Marc
2009-10-28
GMO quantification, based on real-time PCR, relies on the amplification of an event-specific transgene assay and a species-specific reference assay. The uniformity of the nucleotide sequences targeted by both assays across various transgenic varieties is an important prerequisite for correct quantification. Single nucleotide polymorphisms (SNPs) frequently occur in the maize genome and might lead to nucleotide variation in regions used to design primers and probes for reference assays. Further, they may affect the annealing of the primer to the template and reduce the efficiency of DNA amplification. We assessed the effect of a minor DNA template modification, such as a single base pair mismatch in the primer attachment site, on real-time PCR quantification. A model system was used based on the introduction of artificial mismatches between the forward primer and the DNA template in the reference assay targeting the maize starch synthase (SSIIb) gene. The results show that the presence of a mismatch between the primer and the DNA template causes partial to complete failure of the amplification of the initial DNA template depending on the type and location of the nucleotide mismatch. With this study, we show that the presence of a primer/template mismatch affects the estimated total DNA quantity to a varying degree.
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Peptide-templated noble metal catalysts: syntheses and applications
Wang, Wei; Anderson, Caleb F.; Wang, Zongyuan; Wu, Wei
2017-01-01
Noble metal catalysts have been widely used in many applications because of their high activity and selectivity. However, a controllable preparation of noble metal catalysts still remains as a significant challenge. To overcome this challenge, peptide templates can play a critical role in the controllable syntheses of catalysts owing to their flexible binding with specific metallic surfaces and self-assembly characteristics. By employing peptide templates, the size, shape, facet, structure, and composition of obtained catalysts can all be specifically controlled under the mild synthesis conditions. In addition, catalysts with spherical, nanofiber, and nanofilm structures can all be produced by associating with the self-assembly characteristics of peptide templates. Furthermore, the peptide-templated noble metal catalysts also reveal significantly enhanced catalytic behaviours compared with conventional catalysts because the electron conductivity, metal dispersion, and reactive site exposure can all be improved. In this review, we summarize the research progresses in the syntheses of peptide-templated noble metal catalysts. The applications of the peptide-templated catalysts in organic reactions, photocatalysis, and electrocatalysis are discussed, and the relationship between structure and activity of these catalysts are addressed. Future opportunities, including new catalytic materials designed by using biological principles, are indicated to achieve selective, eco-friendly, and energy neutral synthesis approaches. PMID:28507701
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Ligand design by a combinatorial approach based on modeling and experiment: application to HLA-DR4
NASA Astrophysics Data System (ADS)
Evensen, Erik; Joseph-McCarthy, Diane; Weiss, Gregory A.; Schreiber, Stuart L.; Karplus, Martin
2007-07-01
Combinatorial synthesis and large scale screening methods are being used increasingly in drug discovery, particularly for finding novel lead compounds. Although these "random" methods sample larger areas of chemical space than traditional synthetic approaches, only a relatively small percentage of all possible compounds are practically accessible. It is therefore helpful to select regions of chemical space that have greater likelihood of yielding useful leads. When three-dimensional structural data are available for the target molecule this can be achieved by applying structure-based computational design methods to focus the combinatorial library. This is advantageous over the standard usage of computational methods to design a small number of specific novel ligands, because here computation is employed as part of the combinatorial design process and so is required only to determine a propensity for binding of certain chemical moieties in regions of the target molecule. This paper describes the application of the Multiple Copy Simultaneous Search (MCSS) method, an active site mapping and de novo structure-based design tool, to design a focused combinatorial library for the class II MHC protein HLA-DR4. Methods for the synthesizing and screening the computationally designed library are presented; evidence is provided to show that binding was achieved. Although the structure of the protein-ligand complex could not be determined, experimental results including cross-exclusion of a known HLA-DR4 peptide ligand (HA) by a compound from the library. Computational model building suggest that at least one of the ligands designed and identified by the methods described binds in a mode similar to that of native peptides.
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Sampling and energy evaluation challenges in ligand binding protein design
Dou, Jiayi; Doyle, Lindsey; Jr. Greisen, Per; Schena, Alberto; Park, Hahnbeom; Johnsson, Kai; Stoddard, Barry L.
2017-01-01
Abstract The steroid hormone 17α‐hydroxylprogesterone (17‐OHP) is a biomarker for congenital adrenal hyperplasia and hence there is considerable interest in development of sensors for this compound. We used computational protein design to generate protein models with binding sites for 17‐OHP containing an extended, nonpolar, shape‐complementary binding pocket for the four‐ring core of the compound, and hydrogen bonding residues at the base of the pocket to interact with carbonyl and hydroxyl groups at the more polar end of the ligand. Eight of 16 designed proteins experimentally tested bind 17‐OHP with micromolar affinity. A co‐crystal structure of one of the designs revealed that 17‐OHP is rotated 180° around a pseudo‐two‐fold axis in the compound and displays multiple binding modes within the pocket, while still interacting with all of the designed residues in the engineered site. Subsequent rounds of mutagenesis and binding selection improved the ligand affinity to nanomolar range, while appearing to constrain the ligand to a single bound conformation that maintains the same “flipped” orientation relative to the original design. We trace the discrepancy in the design calculations to two sources: first, a failure to model subtle backbone changes which alter the distribution of sidechain rotameric states and second, an underestimation of the energetic cost of desolvating the carbonyl and hydroxyl groups of the ligand. The difference between design model and crystal structure thus arises from both sampling limitations and energy function inaccuracies that are exacerbated by the near two‐fold symmetry of the molecule. PMID:28980354
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Yannas, IV; Tzeranis, D; So, PT
2018-01-01
We review the details of preparation and of the recently elucidated mechanism of biological (regenerative) activity of a collagen scaffold (dermis regeneration template, DRT) that has induced regeneration of skin and peripheral nerves (PN) in a variety of animal models and in the clinic. DRT is a 3D protein network with optimized pore size in the range 20–125 μm, degradation half-life 14 ± 7 d and ligand densities that exceed 200 μ α1β1 or α2β1 ligands. The pore has been optimized to allow migration of contractile cells (myofibroblasts, MFB) into the scaffold and to provide sufficient specific surface for cell–scaffold interaction; the degradation half-life provides the required time window for satisfactory binding interaction of MFB with the scaffold surface; and the ligand density supplies the appropriate ligands for specific binding of MFB on the scaffold surface. A dramatic change in MFB phenotype takes place following MFB-scaffold binding which has been shown to result in blocking of wound contraction. In both skin wounds and PN wounds the evidence has shown clearly that contraction blocking by DRT is followed by induction of regeneration of nearly perfect organs. The biologically active structure of DRT is required for contraction blocking; well-matched collagen scaffold controls of DRT, with structures that varied from that of DRT, have failed to induce regeneration. Careful processing of collagen scaffolds is required for adequate biological activity of the scaffold surface. The newly understood mechanism provides a relatively complete paradigm of regenerative medicine that can be used to prepare scaffolds that may induce regeneration of other organs in future studies. PMID:26694657
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Wilczynski, Andrzej; Wilson, Krista R; Scott, Joseph W; Edison, Arthur S; Haskell-Luevano, Carrie
2005-04-21
The melanocortin receptor system consists of endogenous agonists, antagonists, G-protein coupled receptors, and auxiliary proteins that are involved in the regulation of complex physiological functions such as energy and weight homeostasis, feeding behavior, inflammation, sexual function, pigmentation, and exocrine gland function. Herein, we report the structure-activity relationship (SAR) of a new chimeric hAGRP-melanocortin agonist peptide template Tyr-c[beta-Asp-His-DPhe-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) that was characterized using amino acids previously reported in other melanocortin agonist templates. Twenty peptides were examined in this study, and six peptides were selected for (1)H NMR and computer-assisted molecular modeling structural analysis. The most notable results include the identification that modification of the chimeric template at the His position with Pro and Phe resulted in ligands that were nM mouse melanocortin-3 receptor (mMC3R) antagonists and nM mouse melanocortin-4 receptor (mMC4R) agonists. The peptides Tyr-c[beta-Asp-His-DPhe-Ala-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) and Tyr-c[beta-Asp-His-DNal(1')-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) resulted in 730- and 560-fold, respectively, mMC4R versus mMC3R selective agonists that also possessed nM agonist potency at the mMC1R and mMC5R. Structural studies identified a reverse turn occurring in the His-DPhe-Arg-Trp domain, with subtle differences observed that may account for the differences in melanocortin receptor pharmacology. Specifically, a gamma-turn secondary structure involving the DPhe(4) in the central position of the Tyr-c[beta-Asp-Phe-DPhe-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) peptide may differentiate the mixed mMC3R antagonist and mMC4R agonist pharmacology.
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Armen, Roger S.; Schiller, Stefan M.; Brooks, Charles L.
2015-01-01
Orthogonal aminoacyl-tRNA synthetase/tRNA pairs from archaea have been evolved to facilitate site specific in vivo incorporation of unnatural amino acids into proteins in Escherichia coli. Using this approach, unnatural amino acids have been successfully incorporated with high translational efficiency and fidelity. In this study, CHARMM-based molecular docking and free energy calculations were used to evaluate rational design of specific protein-ligand interactions for aminoacyl-tRNA synthetases. A series of novel unnatural amino acid ligands were docked into the p-benzoyl-L-phenylalanine tRNA synthetase, which revealed that the binding pocket of the enzyme does not provide sufficient space for significantly larger ligands. Specific binding site residues were mutated to alanine to create additional space to accommodate larger target ligands, and then mutations were introduced to improve binding free energy. This approach was used to redesign binding sites for several different target ligands, which were then tested against the standard 20 amino acids to verify target specificity. Only the synthetase designed to bind Man-α-O-Tyr was predicted to be sufficiently selective for the target ligand and also thermodynamically stable. Our study suggests that extensive redesign of the tRNA synthatase binding pocket for large bulky ligands may be quite thermodynamically unfavorable. PMID:20310065
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Principles for designing proteins with cavities formed by curved β sheets
DOE Office of Scientific and Technical Information (OSTI.GOV)
Marcos, Enrique; Basanta, Benjamin; Chidyausiku, Tamuka M.
Active sites and ligand-binding cavities in native proteins are often formed by curved β sheets, and the ability to control β-sheet curvature would allow design of binding proteins with cavities customized to specific ligands. Toward this end, we investigated the mechanisms controlling β-sheet curvature by studying the geometry of β sheets in naturally occurring protein structures and folding simulations. The principles emerging from this analysis were used to design, de novo, a series of proteins with curved β sheets topped with α helices. Nuclear magnetic resonance and crystal structures of the designs closely match the computational models, showing that β-sheetmore » curvature can be controlled with atomic-level accuracy. Our approach enables the design of proteins with cavities and provides a route to custom design ligand-binding and catalytic sites.« less
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Deng, Ting; Jiang, Minghui; Lei, Qing; Cai, Lihong; Chen, Li
2016-12-01
Clinical trial for cervical screw insertion by using individualized 3-dimensional (3D) printing screw insertion templates device. The objective of this study is to evaluate the safety and accuracy of the individualized 3D printing screw insertion template in the cervical spine. Ten patients who underwent posterior cervical fusion surgery with cervical pedicle screws, laminar screws or lateral mass screws between December 2014 and December 2015 were involved in this study. The patients were examined by CT scan before operation. The individualized 3D printing templates were made with photosensitive resin by a 3D printing system to ensure the screw shafts entered the vertebral body without breaking the pedicle or lamina cortex. The templates were sterilized by a plasma sterilizer and used during the operation. The accuracy and the safety of the templates were evaluated by CT scans at the screw insertion levels after operation. The accuracy of this patient-specific template technique was demonstrated. Only one screw axis greatly deviated from the planned track and breached the cortex of the pedicle because the template was split by rough handling and then we inserted the screws under the fluoroscopy. The remaining screws were inserted in the track as preoperative design and the screw axis deviated by less than 2 mm. Vascular or neurologic complications or injuries did not happen. And no infection, broken nails, fracture of bone structure, or screw pullout occurred. This study verified the safety and the accuracy of the individualized 3D printing screw insertion templates in the cervical spine as a kind of intraoperative screw navigation. This individualized 3D printing screw insertion template was user-friendly, moderate cost, and enabled a radiation-free cervical screw insertion.
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Balakrishnan, Mini; Roques, Bernard P.; Fay, Philip J.; Bambara, Robert A.
2003-01-01
The biochemical mechanism of template switching by human immunodeficiency virus type 1 (HIV-1) reverse transcriptase and the role of template dimerization were examined. Homologous donor-acceptor template pairs derived from the HIV-1 untranslated leader region and containing the wild-type and mutant dimerization initiation sequences (DIS) were used to examine the efficiency and distribution of transfers. Inhibiting donor-acceptor interaction was sufficient to reduce transfers in DIS-containing template pairs, indicating that template dimerization, and not the mere presence of the DIS, promotes efficient transfers. Additionally, we show evidence that the overall transfer process spans an extended region of the template and proceeds through a two-step mechanism. Transfer is initiated through an RNase H-facilitated acceptor invasion step, while synthesis continues on the donor template. The invasion then propagates towards the primer terminus by branch migration. Transfer is completed with the translocation of the primer terminus at a site distant from the invasion point. In our system, most invasions initiated before synthesis reached the DIS. However, transfer of the primer terminus predominantly occurred after synthesis through the DIS. The two steps were separated by 60 to 80 nucleotides. Sequence markers revealed the position of primer terminus switch, whereas DNA oligomers designed to block acceptor-cDNA interactions defined sites of invasion. Within the region of homology, certain positions on the template were inherently more favorable for invasion than others. In templates with DIS, the proximity of the acceptor facilitates invasion, thereby enhancing transfer efficiency. Nucleocapsid protein enhanced the overall efficiency of transfers but did not alter the mechanism. PMID:12663778
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Boiocchi, Massimo; Fabbrizzi, Luigi; Garolfi, Mauro; Licchelli, Maurizio; Mosca, Lorenzo; Zanini, Cristina
2009-10-26
Copper(II) azacyclam complexes 3(2+) and 4(2+) were obtained through a metal-templated procedure involving the pertinent open-chain tetramine, formaldehyde and a phenylurea derivative as a locking fragment. Both metal complexes can establish interactions with anions through the metal centre and the amide NH group. Equilibrium studies in DMSO by a spectrophotometric titration technique were carried out to assess the affinity of 3(2+) and 4(2+) towards anions. While the NH group of an amide model compound and the metal centre of the plain Cu(II)(azacyclam)(2+) complex do not interact at all with anions, 3(2+) and 4(2+) establish strong interactions with oxo anions, profiting from a pronounced cooperative effect. In particular, 1) they form stable 1:1 and 1:2 complexes with H(2)PO(4) (-) ions in a stepwise mode with both hydrogen-bonding and metal-ligand interactions, and 2) in the presence of CH(3)COO(-), they undergo deprotonation of the amido NH group and thus profit from axial coordination of the partially negatively charged carbonyl oxygen atom in a scorpionate binding mode.
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Silalahi, Rhone P Brocha; Chakrahari, Kiran Kumarvarma; Liao, Jian-Hong; Kahlal, Samia; Liu, Yu-Chiao; Chiang, Ming-Hsi; Saillard, Jean-Yves; Liu, C W
2018-03-02
Atomically precise Cu-rich bimetallic superatom clusters have been synthesized by adopting a galvanic exchange strategy. [Cu@Cu 12 (S 2 CN n Bu 2 ) 6 (C≡CPh) 4 ][CuCl 2 ] (1) was used as a template to generate compositionally uniform clusters [M@Cu 12 (S 2 CN n Bu 2 ) 6 (C≡CPh) 4 ][CuCl 2 ], where M=Ag (2), Au (3). Structures of 1, 2 and 3 were determined by single crystal X-ray diffraction and the results were supported by ESI-MS. The anatomies of clusters 1-3 are very similar, with a centred cuboctahedral cationic core that is surrounded by six di-butyldithiocarbamate (dtc) and four phenylacetylide ligands. The doped Ag and Au atoms were found to preferentially occupy the centre of the 13-atom cuboctahedral core. Experimental and theoretical analyses of the synthesized clusters revealed that both Ag and Au doping result in significant changes in cluster stability, optical characteristics and enhancement in luminescence properties. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Bootharaju, Megalamane S; Joshi, Chakra P; Parida, Manas R; Mohammed, Omar F; Bakr, Osman M
2016-01-18
Synthesis of atom-precise alloy nanoclusters with uniform composition is challenging when the alloying atoms are similar in size (for example, Ag and Au). A galvanic exchange strategy has been devised to produce a compositionally uniform [Ag24Au(SR)18](-) cluster (SR: thiolate) using a pure [Ag25(SR)18](-) cluster as a template. Conversely, the direct synthesis of Ag24Au cluster leads to a mixture of [Ag(25-x)Au(x)(SR)18](-), x=1-8. Mass spectrometry and crystallography of [Ag24Au(SR)18](-) reveal the presence of the Au heteroatom at the Ag25 center, forming Ag24Au. The successful exchange of the central Ag of Ag25 with Au causes perturbations in the Ag25 crystal structure, which are reflected in the absorption, luminescence, and ambient stability of the particle. These properties are compared with those of Ag25 and Ag24Pd clusters with same ligand and structural framework, providing new insights into the modulation of cluster properties with dopants at the single-atom level. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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De novo design of molecular architectures by evolutionary assembly of drug-derived building blocks.
Schneider, G; Lee, M L; Stahl, M; Schneider, P
2000-07-01
An evolutionary algorithm was developed for fragment-based de novo design of molecules (TOPAS, TOPology-Assigning System). This stochastic method aims at generating a novel molecular structure mimicking a template structure. A set of approximately 25,000 fragment structures serves as the building block supply, which were obtained by a straightforward fragmentation procedure applied to 36,000 known drugs. Eleven reaction schemes were implemented for both fragmentation and building block assembly. This combination of drug-derived building blocks and a restricted set of reaction schemes proved to be a key for the automatic development of novel, synthetically tractable structures. In a cyclic optimization process, molecular architectures were generated from a parent structure by virtual synthesis, and the best structure of a generation was selected as the parent for the subsequent TOPAS cycle. Similarity measures were used to define 'fitness', based on 2D-structural similarity or topological pharmacophore distance between the template molecule and the variants. The concept of varying library 'diversity' during a design process was consequently implemented by using adaptive variant distributions. The efficiency of the design algorithm was demonstrated for the de novo construction of potential thrombin inhibitors mimicking peptide and non-peptide template structures.
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Robust Visual Tracking Revisited: From Correlation Filter to Template Matching.
Liu, Fanghui; Gong, Chen; Huang, Xiaolin; Zhou, Tao; Yang, Jie; Tao, Dacheng
2018-06-01
In this paper, we propose a novel matching based tracker by investigating the relationship between template matching and the recent popular correlation filter based trackers (CFTs). Compared to the correlation operation in CFTs, a sophisticated similarity metric termed mutual buddies similarity is proposed to exploit the relationship of multiple reciprocal nearest neighbors for target matching. By doing so, our tracker obtains powerful discriminative ability on distinguishing target and background as demonstrated by both empirical and theoretical analyses. Besides, instead of utilizing single template with the improper updating scheme in CFTs, we design a novel online template updating strategy named memory, which aims to select a certain amount of representative and reliable tracking results in history to construct the current stable and expressive template set. This scheme is beneficial for the proposed tracker to comprehensively understand the target appearance variations, recall some stable results. Both qualitative and quantitative evaluations on two benchmarks suggest that the proposed tracking method performs favorably against some recently developed CFTs and other competitive trackers.
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Wan, Mimi; Zhao, Wenbo; Peng, Fang; Wang, Qi; Xu, Ping; Mao, Chun; Shen, Jian
2016-01-01
A new kind of high-quality Ag/PS coaxial nanocables can be facilely synthesized by using soft/hard templates method. In order to effectively introduce Ag sources into porous polystyrene (PS) nanotubes which were trapped in porous anodic aluminum oxide (AAO) hard template, Pluronic F127 (F127) was used as guiding agent, soft template and reductant. Meanwhile, ethylene glycol solution was also used as solvent and co-reducing agent to assist in the formation of silver nanowires. The influences of concentration of F127 and reducing reaction time on the formation of Ag/PS coaxial nanocables were discussed. Results indicated that the high-quality Ag/PS coaxial nanocables can be obtained by the mixed mode of soft/hard templates under optimized conditions. This strategy is expected to be extended to design more metal/polymer coaxial nanocables for the benefit of creation of complex and functional nanoarchitectures and components. PMID:27477888
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Huang, Haiqing; Liu, Xiaoyan; Huang, Jianguo, E-mail: jghuang@zju.edu.cn
Graphical abstract: Bio-inspired, tubular structured hierarchical mesoporous titania material with high photocatalytic activity under UV light was fabricated employing natural cellulosic substance (cotton) as hard template and cetyltrimethylammonium bromide (CTAB) surfactant as soft template using a one-pot sol-gel method. Highlights: {yields} Tubular structured mesoporous titania material was fabricated by sol-gel method. {yields} The titania material faithfully recorded the hierarchical structure of the template substrate (cotton). {yields} The titania material exhibited high photocatalytic activity in decomposition of methylene blue. -- Abstract: Bio-inspired, tubular structured hierarchical mesoporous titania material was designed and fabricated employing natural cellulosic substance (cotton) as hard template andmore » cetyltrimethylammonium bromide (CTAB) surfactant as soft template by one-pot sol-gel method. The tubular structured hierarchical mesoporous titania material processes large specific surface area (40.23 m{sup 2}/g) and shows high photocatalytic activity in the photodegradation of methylene blue under UV light irradiation.« less
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Agrawal, Sangeeta; Bhatnagar, Rishi Raj; Tiwari, Anjani; Srivastava, Rakesh; Sharma, Upasana
2013-11-01
Benzimidazole and their metal analogs that can act as multimodal agent and have non-peptidic CCK-B receptor antagonist were synthesized and characterized on the basis of spectroscopic techniques such as FT-IR, NMR, FAB-MS and also evaluated for biologic efficacy. The ligands showed binding to most of the organs, known to express CCK receptors in biodistribution studies. Cholecystokinin (CCK1 and CCK2) receptor binding affinities of these analogs (IC50) are 0.802 ± 0.007 for compound C and 0.326 ± 0.012 for compound D in rat pancreatic acini. These studies have provided a new template for further development of novel agents for various related diseases.
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Computational design of an endo-1,4-[beta]-xylanase ligand binding site
DOE Office of Scientific and Technical Information (OSTI.GOV)
Morin, Andrew; Kaufmann, Kristian W.; Fortenberry, Carie
2012-09-05
The field of computational protein design has experienced important recent success. However, the de novo computational design of high-affinity protein-ligand interfaces is still largely an open challenge. Using the Rosetta program, we attempted the in silico design of a high-affinity protein interface to a small peptide ligand. We chose the thermophilic endo-1,4-{beta}-xylanase from Nonomuraea flexuosa as the protein scaffold on which to perform our designs. Over the course of the study, 12 proteins derived from this scaffold were produced and assayed for binding to the target ligand. Unfortunately, none of the designed proteins displayed evidence of high-affinity binding. Structural characterizationmore » of four designed proteins revealed that although the predicted structure of the protein model was highly accurate, this structural accuracy did not translate into accurate prediction of binding affinity. Crystallographic analyses indicate that the lack of binding affinity is possibly due to unaccounted for protein dynamics in the 'thumb' region of our design scaffold intrinsic to the family 11 {beta}-xylanase fold. Further computational analysis revealed two specific, single amino acid substitutions responsible for an observed change in backbone conformation, and decreased dynamic stability of the catalytic cleft. These findings offer new insight into the dynamic and structural determinants of the {beta}-xylanase proteins.« less
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Development of a remote spectroelectrochemical sensor for technetium as pertechnetate
NASA Astrophysics Data System (ADS)
Monk, David James
Subsurface contamination by technetium (Tc) is of particular concern in the monitoring, characterization, and remediation of underground nuclear waste storage tanks, processing areas, and associated surroundings at the Hanford Site and other U.S. DOE sites nationwide. The concern over this radioactive element arises for two reasons. First, its most common isotope, 99Tc, has an extremely long lifetime of 2.15 x 105 years. Second, it's most common chemical form in environmental conditions, pertechnetate (TcO4-), exhibits very fast migration through soils and readily presents itself to any nearby aquifer. Standard procedures of sampling and analysis in a laboratory prove to be slow and costly in the case of subsurface contamination by radioactive materials. It is highly desirable to develop sensors for these materials that possess the capability of either in-situ or on-site placement for continuous monitoring or immediate analysis of collected samples. These sensors need to possess adequate detection limit and selectivity, rapid response, reversibility (many measurements with one sensor), the ability to perform remotely, and ruggedness. This dissertation describes several areas of the continued work toward a sensor for 99Tc as TcO4-. Research initially focused on developing spectroelectrochemical instrumentation and a disposable sensing element, engineered to address the need to perform remote measurements. The instrument was then tested using samples containing 99Tc, resulting in the development of ancillary equipment and techniques to address concerns associated with performing experiments on radioactive materials. In these tests, the electrochemistry of TcO4 - was demonstrated to be irreversible. Electrochemical reduction of TcO4- on a bare or polymer modified electrode resulted in the continuous build up of technetium oxide (TcO2) on the electrode surface. This TcO2 formed in visual quantities in these films during electrochemistry, and proved to be non-ideal for spectroelectrochemical sensing. In the most recent work described, the development of metal templating techniques using complexes synthesized with rhenium (Re) was investigated as one means to circumvent this irreversibility. In an extension of the metal templating research, custom ligands were being designed which will impart structural rigidity and fluorescence to the template complexes, to facilitate selectivity and sensitivity at levels previously unprecedented for optical techniques.
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RNA Nanotechnology: Engineering, Assembly and Applications in Detection, Gene Delivery and Therapy
Guo, Peixuan
2010-01-01
Biological macromolecules including DNA, RNA, and proteins, have intrinsic features that make them potential building blocks for the bottom-up fabrication of nanodevices. RNA is unique in nanoscale fabrication due to its amazing diversity of function and structure. RNA molecules can be designed and manipulated with a level of simplicity characteristic of DNA while possessing versatility in structure and function similar to that of proteins. RNA molecules typically contain a large variety of single stranded loops suitable for inter- and intra-molecular interaction. These loops can serve as mounting dovetails obviating the need for external linking dowels in fabrication and assembly. The self-assembly of nanoparticles from RNA involves cooperative interaction of individual RNA molecules that spontaneously assemble in a predefined manner to form a larger two- or three-dimensional structure. Within the realm of self-assembly there are two main categories, namely template and non-template. Template assembly involves interaction of RNA molecules under the influence of specific external sequence, forces, or spatial constraints such as RNA transcription, hybridization, replication, annealing, molding, or replicas. In contrast, non-template assembly involves formation of a larger structure by individual components without the influence of external forces. Examples of non-template assembly are ligation, chemical conjugation, covalent linkage, and loop/loop interaction of RNA, especially the formation of RNA multimeric complexes. The best characterized RNA multiplier and the first to be described in RNA nanotechnological application is the motor pRNA of bacteriophage phi29 which form dimers, trimers, and hexamers, via hand-in-hand interaction. phi29 pRNA can be redesigned to form a variety of structures and shapes including twins, tetramers, rods, triangles, and 3D arrays several microns in size via interaction of programmed helical regions and loops. 3D RNA array formation requires a defined nucleotide number for twisting and a palindromic sequence. Such arrays are unusually stable and resistant to a wide range of temperatures, salt concentrations, and pH. Both the therapeutic siRNA or ribozyme and a receptor-binding RNA aptamer or other ligands have been engineered into individual pRNAs. Individual chimeric RNA building blocks harboring siRNA or other therapeutic molecules have been fabricated subsequently into a trimer through hand-in-hand interaction of the engineered right and left interlocking RNA loops. The incubation of these particles containing the receptor-binding aptamer or other ligands results in the binding and co-entry of trivalent therapeutic particles into cells. Such particles were subsequently shown to modulate the apoptosis of cancer cells in both cell cultures and animal trials. The use of such antigen-free 20–40 nm particles holds promise for the repeated long-term treatment of chronic diseases. Other potentially useful RNA molecules that form multimers include HIV RNA that contain kissing loop to form dimers, tecto-RNA that forms a “jigsaw puzzle,” and the Drosophila bicoid mRNA that forms multimers via “hand-by-arm” interactions. Applications of RNA molecules involving replication, molding, embossing, and other related techniques, have recently been described that allow the utilization of a variety of materials to enhance diversity and resolution of nanomaterials. It should eventually be possible to adapt RNA to facilitate construction of ordered, patterned, or pre-programmed arrays or superstructures. Given the potential for 3D fabrication, the chance to produce reversible self-assembly, and the ability of self-repair, editing and replication, RNA self-assembly will play an increasingly significant role in integrated biological nanofabrication. A random 100-nucleotide RNA library may exist in 1.6 × 1060 varieties with multifarious structure to serve as a vital system for efficient fabrication, with a complexity and diversity far exceeding that of any current nanoscale system. This review covers the basic concepts of RNA structure and function, certain methods for the study of RNA structure, the approaches for engineering or fabricating RNA into nanoparticles or arrays, and special features of RNA molecules that form multimers. The most recent development in exploration of RNA nanoparticles for pathogen detection, drug/gene delivery, and therapeutic application is also introduced in this review. PMID:16430131
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Ghosh, Arun K.; Parham, Garth L.; Martyr, Cuthbert D.; Nyalapatla, Prasanth R.; Osswald, Heather L.; Agniswamy, Johnson; Wang, Yuan-Fang; Amano, Masayuki; Weber, Irene T.; Mitsuya, Hiroaki
2013-01-01
The design, synthesis, and biological evaluation of a series of HIV-1 protease inhibitors incorporating stereochemically defined fused tricyclic P2-ligands are described. Various substituent effects were investigated in order to maximize the ligand-binding site interactions in the protease active site. Inhibitors 16a and 16f showed excellent enzyme inhibitory and antiviral activity while incorporation of sulfone functionality resulted in a decrease in potency. Both inhibitors 16a and 16f have maintained activity against a panel of multidrug resistant HIV-1 variants. A high-resolution X-ray crystal structure of 16a-bound HIV-1 protease revealed important molecular insights into the ligand-binding site interactions which may account for the inhibitor’s potent antiviral activity and excellent resistance profiles. PMID:23947685
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NASA Astrophysics Data System (ADS)
Carrillo, Alvaro; Gujraty, Kunal V.; Rai, Prakash R.; Kane, Ravi S.
2005-07-01
Multivalent molecules, i.e. scaffolds presenting multiple copies of a suitable ligand, constitute an emerging class of nanoscale therapeutics. We present a novel approach for the design of multivalent ligands, which allows the biofunctionalization of polymers with proteins or peptides in a controlled orientation. It consists of the synthesis of water-soluble, activated polymer scaffolds of controlled molecular weight, which can be biofunctionalized with various thiolated ligands in aqueous media under mild conditions. These polymers were synthesized by ring-opening metathesis polymerization (ROMP) and further modified to make them water-soluble. The incorporation of chloride groups activated the polymers to react with thiol-containing peptides or proteins, and the formation of multivalent ligands in aqueous media was demonstrated. This strategy represents a convenient route for synthesizing multivalent ligands of controlled dimensions and valency.
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Accuracy of femoral templating in reproducing anatomical femoral offset in total hip replacement.
Davies, H; Foote, J; Spencer, R F
2007-01-01
Restoration of hip biomechanics is a crucial component of successful total hip replacement. Preoperative templating is recommended to ensure that the size and orientation of implants is optimised. We studied how closely natural femoral offset could be reproduced using the manufacturers' templates for 10 femoral stems in common use in the UK. A series of 23 consecutive preoperative radiographs from patients who had undergone unilateral total hip replacement for unilateral osteoarthritis of the hip was employed. The change in offset between the templated position of the best-fitting template and the anatomical centre of the hip was measured. The templates were then ranked according to their ability to reproduce the normal anatomical offset. The most accurate was the CPS-Plus (Root Mean Square Error 2.0 mm) followed in rank order by: C stem (2.16), CPT (2.40), Exeter (3.23), Stanmore (3.28), Charnley (3.65), Corail (3.72), ABG II (4.30), Furlong HAC (5.08) and Furlong modular (7.14). A similar pattern of results was achieved when the standard error of variability of offset was analysed. We observed a wide variation in the ability of the femoral prosthesis templates to reproduce normal femoral offset. This variation was independent of the seniority of the observer. The templates of modern polished tapered stems with high modularity were best able to reproduce femoral offset. The current move towards digitisation of X-rays may offer manufacturers an opportunity to improve template designs in certain instances, and to develop appropriate computer software.
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NASA Astrophysics Data System (ADS)
Poornima, C. S.; Dean, P. M.
1995-12-01
Water molecules are known to play an important rôle in mediating protein-ligand interactions. If water molecules are conserved at the ligand-binding sites of homologous proteins, such a finding may suggest the structural importance of water molecules in ligand binding. Structurally conserved water molecules change the conventional definition of `binding sites' by changing the shape and complementarity of these sites. Such conserved water molecules can be important for site-directed ligand/drug design. Therefore, five different sets of homologous protein/protein-ligand complexes have been examined to identify the conserved water molecules at the ligand-binding sites. Our analysis reveals that there are as many as 16 conserved water molecules at the FAD binding site of glutathione reductase between the crystal structures obtained from human and E. coli. In the remaining four sets of high-resolution crystal structures, 2-4 water molecules have been found to be conserved at the ligand-binding sites. The majority of these conserved water molecules are either bound in deep grooves at the protein-ligand interface or completely buried in cavities between the protein and the ligand. All these water molecules, conserved between the protein/protein-ligand complexes from different species, have identical or similar apolar and polar interactions in a given set. The site residues interacting with the conserved water molecules at the ligand-binding sites have been found to be highly conserved among proteins from different species; they are more conserved compared to the other site residues interacting with the ligand. These water molecules, in general, make multiple polar contacts with protein-site residues.
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Qian, S.; Dunham, M.E.
1996-11-12
A system and method are disclosed for constructing a bank of filters which detect the presence of signals whose frequency content varies with time. The present invention includes a novel system and method for developing one or more time templates designed to match the received signals of interest and the bank of matched filters use the one or more time templates to detect the received signals. Each matched filter compares the received signal x(t) with a respective, unique time template that has been designed to approximate a form of the signals of interest. The robust time domain template is assumed to be of the order of w(t)=A(t)cos(2{pi}{phi}(t)) and the present invention uses the trajectory of a joint time-frequency representation of x(t) as an approximation of the instantaneous frequency function {phi}{prime}(t). First, numerous data samples of the received signal x(t) are collected. A joint time frequency representation is then applied to represent the signal, preferably using the time frequency distribution series. The joint time-frequency transformation represents the analyzed signal energy at time t and frequency f, P(t,f), which is a three-dimensional plot of time vs. frequency vs. signal energy. Then P(t,f) is reduced to a multivalued function f(t), a two dimensional plot of time vs. frequency, using a thresholding process. Curve fitting steps are then performed on the time/frequency plot, preferably using Levenberg-Marquardt curve fitting techniques, to derive a general instantaneous frequency function {phi}{prime}(t) which best fits the multivalued function f(t). Integrating {phi}{prime}(t) along t yields {phi}{prime}(t), which is then inserted into the form of the time template equation. A suitable amplitude A(t) is also preferably determined. Once the time template has been determined, one or more filters are developed which each use a version or form of the time template. 7 figs.
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Computer templates in chronic disease management: ethnographic case study in general practice
Swinglehurst, Deborah; Greenhalgh, Trisha; Roberts, Celia
2012-01-01
Objective To investigate how electronic templates shape, enable and constrain consultations about chronic diseases. Design Ethnographic case study, combining field notes, video-recording, screen capture with a microanalysis of talk, body language and data entry—an approach called linguistic ethnography. Setting Two general practices in England. Participants and methods Ethnographic observation of administrative areas and 36 nurse-led consultations was done. Twenty-four consultations were directly observed and 12 consultations were video-recorded alongside computer screen capture. Consultations were transcribed using conversation analysis conventions, with notes on body language and the electronic record. The analysis involved repeated rounds of viewing video, annotating field notes, transcription and microanalysis to identify themes. The data was interpreted using discourse analysis, with attention to the sociotechnical theory. Results Consultations centred explicitly or implicitly on evidence-based protocols inscribed in templates. Templates did not simply identify tasks for completion, but contributed to defining what chronic diseases were, how care was being delivered and what it meant to be a patient or professional in this context. Patients’ stories morphed into data bytes; the particular became generalised; the complex was made discrete, simple and manageable; and uncertainty became categorised and contained. Many consultations resembled bureaucratic encounters, primarily oriented to completing data fields. We identified a tension, sharpened by the template, between different framings of the patient—as ‘individual’ or as ‘one of a population’. Some clinicians overcame this tension, responding creatively to prompts within a dialogue constructed around the patient's narrative. Conclusions Despite their widespread implementation, little previous research has examined how templates are actually used in practice. Templates do not simply document the tasks of chronic disease management but profoundly change the nature of this work. Designed to assure standards of ‘quality’ care they contribute to bureaucratisation of care and may marginalise aspects of quality care which lie beyond their focus. Creative work is required to avoid privileging ‘institution-centred’ care over patient-centred care. PMID:23192245
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Rodriguez Torres, Yasaira; Huang, Jordan; Mihlstin, Melanie; Juzych, Mark S; Kromrei, Heidi; Hwang, Frank S
2017-01-01
This study aimed to determine the role of electronic health record software in resident education by evaluating documentation of 30 elements extracted from the American Academy of Ophthalmology Dry Eye Syndrome Preferred Practice Pattern. The Kresge Eye Institute transitioned to using electronic health record software in June 2013. We evaluated the charts of 331 patients examined in the resident ophthalmology clinic between September 1, 2011, and March 31, 2014, for an initial evaluation for dry eye syndrome. We compared documentation rates for the 30 evidence-based elements between electronic health record chart note templates among the ophthalmology residents. Overall, significant changes in documentation occurred when transitioning to a new version of the electronic health record software with average compliance ranging from 67.4% to 73.6% (p < 0.0005). Electronic Health Record A had high compliance (>90%) in 13 elements while Electronic Health Record B had high compliance (>90%) in 11 elements. The presence of dialog boxes was responsible for significant changes in documentation of adnexa, puncta, proptosis, skin examination, contact lens wear, and smoking exposure. Significant differences in documentation were correlated with electronic health record template design rather than individual resident or residents' year in training. Our results show that electronic health record template design influences documentation across all resident years. Decreased documentation likely results from "mouse click fatigue" as residents had to access multiple dialog boxes to complete documentation. These findings highlight the importance of EHR template design to improve resident documentation and integration of evidence-based medicine into their clinical notes.
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NASA Technical Reports Server (NTRS)
Scola, Salvatore; Stavely, Rebecca; Jackson, Trevor; Boyer, Charlie; Osmundsen, Jim; Turczynski, Craig; Stimson, Chad
2016-01-01
Performance-related effects of system level temperature changes can be a key consideration in the design of many types of optical instruments. This is especially true for space-based imagers, which may require complex thermal control systems to maintain alignment of the optical components. Structural-Thermal-Optical-Performance (STOP) analysis is a multi-disciplinary process that can be used to assess the performance of these optical systems when subjected to the expected design environment. This type of analysis can be very time consuming, which makes it difficult to use as a trade study tool early in the project life cycle. In many cases, only one or two iterations can be performed over the course of a project. This limits the design space to best practices since it may be too difficult, or take too long, to test new concepts analytically. In order to overcome this challenge, automation, and a standard procedure for performing these studies is essential. A methodology was developed within the framework of the Comet software tool that captures the basic inputs, outputs, and processes used in most STOP analyses. This resulted in a generic, reusable analysis template that can be used for design trades for a variety of optical systems. The template captures much of the upfront setup such as meshing, boundary conditions, data transfer, naming conventions, and post-processing, and therefore saves time for each subsequent project. A description of the methodology and the analysis template is presented, and results are described for a simple telescope optical system.
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NASA Astrophysics Data System (ADS)
Scola, Salvatore; Stavely, Rebecca; Jackson, Trevor; Boyer, Charlie; Osmundsen, Jim; Turczynski, Craig; Stimson, Chad
2016-09-01
Performance-related effects of system level temperature changes can be a key consideration in the design of many types of optical instruments. This is especially true for space-based imagers, which may require complex thermal control systems to maintain alignment of the optical components. Structural-Thermal-Optical-Performance (STOP) analysis is a multi-disciplinary process that can be used to assess the performance of these optical systems when subjected to the expected design environment. This type of analysis can be very time consuming, which makes it difficult to use as a trade study tool early in the project life cycle. In many cases, only one or two iterations can be performed over the course of a project. This limits the design space to best practices since it may be too difficult, or take too long, to test new concepts analytically. In order to overcome this challenge, automation, and a standard procedure for performing these studies is essential. A methodology was developed within the framework of the Comet software tool that captures the basic inputs, outputs, and processes used in most STOP analyses. This resulted in a generic, reusable analysis template that can be used for design trades for a variety of optical systems. The template captures much of the upfront setup such as meshing, boundary conditions, data transfer, naming conventions, and post-processing, and therefore saves time for each subsequent project. A description of the methodology and the analysis template is presented, and results are described for a simple telescope optical system.
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40 CFR Appendix C to Subpart Nnn... - Method for the Determination of Product Density
Code of Federal Regulations, 2011 CFR
2011-07-01
... insulation. The method is applicable to all cured board and blanket products. 2. Equipment One square foot (12 in. by 12 in.) template, or templates that are multiples of one square foot, for use in cutting... procedure for the designated product. 3.2Cut samples using one square foot (or multiples of one square foot...
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40 CFR Appendix C to Subpart Nnn... - Method for the Determination of Product Density
Code of Federal Regulations, 2012 CFR
2012-07-01
.... The method is applicable to all cured board and blanket products. 2. Equipment One square foot (12 in. by 12 in.) template, or templates that are multiples of one square foot, for use in cutting... procedure for the designated product. 3.2Cut samples using one square foot (or multiples of one square foot...
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40 CFR Appendix C to Subpart Nnn... - Method for the Determination of Product Density
Code of Federal Regulations, 2010 CFR
2010-07-01
.... The method is applicable to all cured board and blanket products. 2. Equipment One square foot (12 in. by 12 in.) template, or templates that are multiples of one square foot, for use in cutting... procedure for the designated product. 3.2Cut samples using one square foot (or multiples of one square foot...
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Cloud Computing for Protein-Ligand Binding Site Comparison
2013-01-01
The proteome-wide analysis of protein-ligand binding sites and their interactions with ligands is important in structure-based drug design and in understanding ligand cross reactivity and toxicity. The well-known and commonly used software, SMAP, has been designed for 3D ligand binding site comparison and similarity searching of a structural proteome. SMAP can also predict drug side effects and reassign existing drugs to new indications. However, the computing scale of SMAP is limited. We have developed a high availability, high performance system that expands the comparison scale of SMAP. This cloud computing service, called Cloud-PLBS, combines the SMAP and Hadoop frameworks and is deployed on a virtual cloud computing platform. To handle the vast amount of experimental data on protein-ligand binding site pairs, Cloud-PLBS exploits the MapReduce paradigm as a management and parallelizing tool. Cloud-PLBS provides a web portal and scalability through which biologists can address a wide range of computer-intensive questions in biology and drug discovery. PMID:23762824
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Cloud computing for protein-ligand binding site comparison.
Hung, Che-Lun; Hua, Guan-Jie
2013-01-01
The proteome-wide analysis of protein-ligand binding sites and their interactions with ligands is important in structure-based drug design and in understanding ligand cross reactivity and toxicity. The well-known and commonly used software, SMAP, has been designed for 3D ligand binding site comparison and similarity searching of a structural proteome. SMAP can also predict drug side effects and reassign existing drugs to new indications. However, the computing scale of SMAP is limited. We have developed a high availability, high performance system that expands the comparison scale of SMAP. This cloud computing service, called Cloud-PLBS, combines the SMAP and Hadoop frameworks and is deployed on a virtual cloud computing platform. To handle the vast amount of experimental data on protein-ligand binding site pairs, Cloud-PLBS exploits the MapReduce paradigm as a management and parallelizing tool. Cloud-PLBS provides a web portal and scalability through which biologists can address a wide range of computer-intensive questions in biology and drug discovery.
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Moreau, Christophe J.; Revilloud, Jean; Caro, Lydia N.; Dupuis, Julien P.; Trouchet, Amandine; Estrada-Mondragón, Argel; Nieścierowicz, Katarzyna; Sapay, Nicolas; Crouzy, Serge; Vivaudou, Michel
2017-01-01
Ligand-gated ion channels enable intercellular transmission of action potential through synapses by transducing biochemical messengers into electrical signal. We designed artificial ligand-gated ion channels by coupling G protein-coupled receptors to the Kir6.2 potassium channel. These artificial channels called ion channel-coupled receptors offer complementary properties to natural channels by extending the repertoire of ligands to those recognized by the fused receptors, by generating more sustained signals and by conferring potassium selectivity. The first artificial channels based on the muscarinic M2 and the dopaminergic D2L receptors were opened and closed by acetylcholine and dopamine, respectively. We find here that this opposite regulation of the gating is linked to the length of the receptor C-termini, and that C-terminus engineering can precisely control the extent and direction of ligand gating. These findings establish the design rules to produce customized ligand-gated channels for synthetic biology applications. PMID:28145461
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Self-assembly of knots and links
NASA Astrophysics Data System (ADS)
Orlandini, Enzo; Polles, Guido; Marenduzzo, Davide; Micheletti, Cristian
2017-03-01
Guiding the self-assembly of identical building blocks towards complex three-dimensional structures with a set of desired properties is a major goal in material science, chemistry and physics. A particularly challenging problem, especially explored in synthetic chemistry, is that of self-assembling closed structures with a target topology starting by simple geometrical templates. Here we overview and revisit recent advancements, based on stochastic simulations, where the geometry of rigid helical templates with functionalised sticky ends has been designed for self-assembling efficiently and reproducibly into a wide range of three-dimensional closed structures. Notably, these include non trivial topologies of links and knots, including the 819 knot that we had predicted to be highly encodable and that has only recently been obtained experimentally. By appropriately tuning the parameters that define the template shape, we show that, for fixed concentration of templates, the assembly process can be directed towards the formation of specific knotted and linked structures such as the trefoils, pentafoil knots, Hopf and Solomon links. More exotic and unexpected knots and links are also found. Our results should be relevant to the design of new protocols that can both increase and broaden the population of synthetise molecular knots and catenanes.
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Process Materialization Using Templates and Rules to Design Flexible Process Models
NASA Astrophysics Data System (ADS)
Kumar, Akhil; Yao, Wen
The main idea in this paper is to show how flexible processes can be designed by combining generic process templates and business rules. We instantiate a process by applying rules to specific case data, and running a materialization algorithm. The customized process instance is then executed in an existing workflow engine. We present an architecture and also give an algorithm for process materialization. The rules are written in a logic-based language like Prolog. Our focus is on capturing deeper process knowledge and achieving a holistic approach to robust process design that encompasses control flow, resources and data, as well as makes it easier to accommodate changes to business policy.
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Tateishi-Karimata, Hisae; Isono, Noburu; Sugimoto, Naoki
2014-01-01
The thermal stability and topology of non-canonical structures of G-quadruplexes and hairpins in template DNA were investigated, and the effect of non-canonical structures on transcription fidelity was evaluated quantitatively. We designed ten template DNAs: A linear sequence that does not have significant higher-order structure, three sequences that form hairpin structures, and six sequences that form G-quadruplex structures with different stabilities. Templates with non-canonical structures induced the production of an arrested, a slipped, and a full-length transcript, whereas the linear sequence produced only a full-length transcript. The efficiency of production for run-off transcripts (full-length and slipped transcripts) from templates that formed the non-canonical structures was lower than that from the linear. G-quadruplex structures were more effective inhibitors of full-length product formation than were hairpin structure even when the stability of the G-quadruplex in an aqueous solution was the same as that of the hairpin. We considered that intra-polymerase conditions may differentially affect the stability of non-canonical structures. The values of transcription efficiencies of run-off or arrest transcripts were correlated with stabilities of non-canonical structures in the intra-polymerase condition mimicked by 20 wt% polyethylene glycol (PEG). Transcriptional arrest was induced when the stability of the G-quadruplex structure (-ΔG°37) in the presence of 20 wt% PEG was more than 8.2 kcal mol(-1). Thus, values of stability in the presence of 20 wt% PEG are an important indicator of transcription perturbation. Our results further our understanding of the impact of template structure on the transcription process and may guide logical design of transcription-regulating drugs.
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Tateishi-Karimata, Hisae; Isono, Noburu; Sugimoto, Naoki
2014-01-01
The thermal stability and topology of non-canonical structures of G-quadruplexes and hairpins in template DNA were investigated, and the effect of non-canonical structures on transcription fidelity was evaluated quantitatively. We designed ten template DNAs: A linear sequence that does not have significant higher-order structure, three sequences that form hairpin structures, and six sequences that form G-quadruplex structures with different stabilities. Templates with non-canonical structures induced the production of an arrested, a slipped, and a full-length transcript, whereas the linear sequence produced only a full-length transcript. The efficiency of production for run-off transcripts (full-length and slipped transcripts) from templates that formed the non-canonical structures was lower than that from the linear. G-quadruplex structures were more effective inhibitors of full-length product formation than were hairpin structure even when the stability of the G-quadruplex in an aqueous solution was the same as that of the hairpin. We considered that intra-polymerase conditions may differentially affect the stability of non-canonical structures. The values of transcription efficiencies of run-off or arrest transcripts were correlated with stabilities of non-canonical structures in the intra-polymerase condition mimicked by 20 wt% polyethylene glycol (PEG). Transcriptional arrest was induced when the stability of the G-quadruplex structure (−ΔGo 37) in the presence of 20 wt% PEG was more than 8.2 kcal mol−1. Thus, values of stability in the presence of 20 wt% PEG are an important indicator of transcription perturbation. Our results further our understanding of the impact of template structure on the transcription process and may guide logical design of transcription-regulating drugs. PMID:24594642
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Options in virtual 3D, optical-impression-based planning of dental implants.
Reich, Sven; Kern, Thomas; Ritter, Lutz
2014-01-01
If a 3D radiograph, which in today's dentistry often consists of a CBCT dataset, is available for computerized implant planning, the 3D planning should also consider functional prosthetic aspects. In a conventional workflow, the CBCT is done with a specially produced radiopaque prosthetic setup that makes the desired prosthetic situation visible during virtual implant planning. If an exclusively digital workflow is chosen, intraoral digital impressions are taken. On these digital models, the desired prosthetic suprastructures are designed. The entire datasets are virtually superimposed by a "registration" process on the corresponding structures (teeth) in the CBCTs. Thus, both the osseous and prosthetic structures are visible in one single 3D application and make it possible to consider surgical and prosthetic aspects. After having determined the implant positions on the computer screen, a drilling template is designed digitally. According to this design (CAD), a template is printed or milled in CAM process. This template is the first physically extant product in the entire workflow. The article discusses the options and limitations of this workflow.
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Design Automation Using Script Languages. High-Level CAD Templates in Non-Parametric Programs
NASA Astrophysics Data System (ADS)
Moreno, R.; Bazán, A. M.
2017-10-01
The main purpose of this work is to study the advantages offered by the application of traditional techniques of technical drawing in processes for automation of the design, with non-parametric CAD programs, provided with scripting languages. Given that an example drawing can be solved with traditional step-by-step detailed procedures, is possible to do the same with CAD applications and to generalize it later, incorporating references. In today’s modern CAD applications, there are striking absences of solutions for building engineering: oblique projections (military and cavalier), 3D modelling of complex stairs, roofs, furniture, and so on. The use of geometric references (using variables in script languages) and their incorporation into high-level CAD templates allows the automation of processes. Instead of repeatedly creating similar designs or modifying their data, users should be able to use these templates to generate future variations of the same design. This paper presents the automation process of several complex drawing examples based on CAD script files aided with parametric geometry calculation tools. The proposed method allows us to solve complex geometry designs not currently incorporated in the current CAD applications and to subsequently create other new derivatives without user intervention. Automation in the generation of complex designs not only saves time but also increases the quality of the presentations and reduces the possibility of human errors.
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Designing multiple ligands - medicinal chemistry strategies and challenges.
Morphy, Richard; Rankovic, Zoran
2009-01-01
It has been widely recognised over the recent years that parallel modulation of multiple biological targets can be beneficial for treatment of diseases with complex etiologies such as cancer asthma, and psychiatric disease. In this article, current strategies for the generation of ligands with a specific multi-target profile (designed multiple ligands or DMLs) are described and a number of illustrative example are given. Designing multiple ligands is frequently a challenging endeavour for medicinal chemists, with the need to appropriately balance affinity for 2 or more targets whilst obtaining physicochemical and pharmacokinetic properties that are consistent with the administration of an oral drug. Given that the properties of DMLs are influenced to a large extent by the proteomic superfamily to which the targets belong and the lead generation strategy that is pursued, an early assessment of the feasibility of any given DML project is essential.
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Pani, S C; Dimashkieh, M; Mojaleed, F; Al Shammery, F
2015-12-01
This aim was to evaluate preformed metal crowns (PMC) placed under general anaesthesia using an occlusal template in comparison to crowns placed without the use of a template. CONSORT protocols were followed in the design of the study. A total of 60 children between 4-7 years requiring pulpotomy and PMC for all primary molars met the inclusion criteria for this study. The control group comprised patients for whom the PMC were placed without the use of an occlusal template, while in the test group crowns were placed using a polyvinyl siloxane occlusal template. Patients were followed up at 24 h, 7 days, 3 and 6 months. The time taken for the placement of crowns, instances of post-operative discomfort, success or failure of the pulp therapy and loss of any crowns were compared between the groups. The mean time taken for completion of the procedure in the control group was significantly greater than the template group (t = 2.566, p = 0.013). Significantly fewer patients in the template group reported symptoms of discomfort or high points at the 24-h recall; however, these differences were not significant at the 1-week, 3- or 6-month recall. The use of an occlusal template for the placement of multiple PMC under general anaesthesia reduces the time taken for their placement and reduces the incidence of immediate post-operative discomfort.
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CaCO₃ templated micro-beads and -capsules for bioapplications.
Volodkin, Dmitry
2014-05-01
Porous CaCO₃ vaterite microparticles have been introduced a decade ago as sacrificial cores and becoming nowadays as one of the most popular templates to encapsulate bioactive molecules. This is due to the following beneficial features: i) mild decomposition conditions, ii) highly developed surface area, and iii) controlled size as well as easy and chip preparation. Such properties allow one to template and design particles with well tuned material properties in terms of composition, structure, functionality -- the parameters crucially important for bioapplications. This review presents a recent progress in utilizing the CaCO₃ cores for the assembly of micrometer-sized beads and capsules with encapsulated both small drugs and large biomacromolecules. Bioapplications of all the particles for drug delivery, biotechnology, and biosensing as well as future perspectives for templating are addressed. Copyright © 2014. Published by Elsevier B.V.
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Design of monodisperse and well-defined polypeptide-based polyvalent inhibitors of anthrax toxin.
Patke, Sanket; Boggara, Mohan; Maheshwari, Ronak; Srivastava, Sunit K; Arha, Manish; Douaisi, Marc; Martin, Jacob T; Harvey, Ian B; Brier, Matthew; Rosen, Tania; Mogridge, Jeremy; Kane, Ravi S
2014-07-28
The design of polyvalent molecules, presenting multiple copies of a specific ligand, represents a promising strategy to inhibit pathogens and toxins. The ability to control independently the valency and the spacing between ligands would be valuable for elucidating structure-activity relationships and for designing potent polyvalent molecules. To that end, we designed monodisperse polypeptide-based polyvalent inhibitors of anthrax toxin in which multiple copies of an inhibitory toxin-binding peptide were separated by flexible peptide linkers. By tuning the valency and linker length, we designed polyvalent inhibitors that were over four orders of magnitude more potent than the corresponding monovalent ligands. This strategy for the rational design of monodisperse polyvalent molecules may not only be broadly applicable for the inhibition of toxins and pathogens, but also for controlling the nanoscale organization of cellular receptors to regulate signaling and the fate of stem cells. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Xue, Teng; Lin, Zhaoyang; Chiu, Chin-Yi; ...
2017-01-06
Metallic nanoparticles are emerging as an exciting class of heterogeneous catalysts with the potential advantages of exceptional activity, stability, recyclability, and easier separation than homogeneous catalysts. The traditional colloid nanoparticle syntheses usually involve strong surface binding ligands that could passivate the surface active sites and result in poor catalytic activity. The subsequent removal of surface ligands could reactivate the surface but often leads to metal ion leaching and/or severe Ostwald ripening with diminished catalytic activity or poor stability. Molecular ligand engineering represents a powerful strategy for the design of homogeneous molecular catalysts but is insufficiently explored for nanoparticle catalysts tomore » date. We report a systematic investigation on molecular ligand modulation of palladium (Pd) nanoparticle catalysts. Our studies show that β-functional groups of butyric acid ligand on Pd nanoparticles can significantly modulate the catalytic reaction process to modify the catalytic activity and stability for important aerobic reactions. With a β-hydroxybutyric acid ligand, the Pd nanoparticle catalysts exhibit exceptional catalytic activity and stability with an unsaturated turnover number (TON) >3000 for dehydrogenative oxidation of cyclohexenone to phenol, greatly exceeding that of homogeneous Pd(II) catalysts (TON, ~30). This study presents a systematic investigation of molecular ligand modulation of nanoparticle catalysts and could open up a new pathway toward the design and construction of highly efficient and robust heterogeneous catalysts through molecular ligand engineering.« less
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Nissen, Klaus B; Haugaard-Kedström, Linda M; Wilbek, Theis S; Nielsen, Line S; Åberg, Emma; Kristensen, Anders S; Bach, Anders; Jemth, Per; Strømgaard, Kristian
2015-01-01
PDZ domains in general, and those of PSD-95 in particular, are emerging as promising drug targets for diseases such as ischemic stroke. We have previously shown that dimeric ligands that simultaneously target PDZ1 and PDZ2 of PSD-95 are highly potent inhibitors of PSD-95. However, PSD-95 and the related MAGUK proteins contain three consecutive PDZ domains, hence we envisioned that targeting all three PDZ domains simultaneously would lead to more potent and potentially more specific interactions with the MAGUK proteins. Here we describe the design, synthesis and characterization of a series of trimeric ligands targeting all three PDZ domains of PSD-95 and the related MAGUK proteins, PSD-93, SAP-97 and SAP-102. Using our dimeric ligands targeting the PDZ1-2 tandem as starting point, we designed novel trimeric ligands by introducing a PDZ3-binding peptide moiety via a cysteine-derivatized NPEG linker. The trimeric ligands generally displayed increased affinities compared to the dimeric ligands in fluorescence polarization binding experiments and optimized trimeric ligands showed low nanomolar inhibition towards the four MAGUK proteins, thus being the most potent inhibitors described. Kinetic experiments using stopped-flow spectrometry showed that the increase in affinity is caused by a decrease in the dissociation rate of the trimeric ligand as compared to the dimeric ligands, likely reflecting the lower probability of simultaneous dissociation of all three PDZ ligands. Thus, we have provided novel inhibitors of the MAGUK proteins with exceptionally high affinity, which can be used to further elucidate the therapeutic potential of these proteins.
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NASA Astrophysics Data System (ADS)
Vettoretti, Gerolamo; Moroni, Elisabetta; Sattin, Sara; Tao, Jiahui; Agard, David A.; Bernardi, Anna; Colombo, Giorgio
2016-04-01
Controlling biochemical pathways through chemically designed modulators may provide novel opportunities to develop therapeutic drugs and chemical tools. The underlying challenge is to design new molecular entities able to act as allosteric chemical switches that selectively turn on/off functions by modulating the conformational dynamics of their target protein. We examine the origins of the stimulation of ATPase and closure kinetics in the molecular chaperone Hsp90 by allosteric modulators through atomistic molecular dynamics (MD) simulations and analysis of protein-ligand interactions. In particular, we focus on the cross-talk between allosteric ligands and protein conformations and its effect on the dynamic properties of the chaperone’s active state. We examine the impact of different allosteric modulators on the stability, structural and internal dynamics properties of Hsp90 closed state. A critical aspect of this study is the development of a quantitative model that correlates Hsp90 activation to the presence of a certain compound, making use of information on the dynamic adaptation of protein conformations to the presence of the ligand, which allows to capture conformational states relevant in the activation process. We discuss the implications of considering the conformational dialogue between allosteric ligands and protein conformations for the design of new functional modulators.
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Zhang, Zhi-Hai; Gao, Ling-Xiao; Guo, Yuan-Jun; Wang, Wei; Mo, Xiang-Xia
2012-12-01
The template selection is essential in the application of digital micromirror spectrometer. The best theoretical coding H-matrix is not widely used due to acyclic, complex coding and difficult achievement. The noise ratio of best practical S-matrix for improvement is slightly inferior to matrix H. So we designed a new type complementary S-matrix. Through studying its noise improvement theory, the algorithm is proved to have the advantages of both H-matrix and S-matrix. The experiments proved that the SNR can be increased 2.05 times than S-template.
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Plasmonic nanofocusing with a metallic pyramid and an integrated C-shaped aperture
NASA Astrophysics Data System (ADS)
Lindquist, Nathan C.; Johnson, Timothy W.; Nagpal, Prashant; Norris, David J.; Oh, Sang-Hyun
2013-05-01
We demonstrate the design, fabrication and characterization of a near-field plasmonic nanofocusing probe with a hybrid tip-plus-aperture design. By combining template stripping with focused ion beam lithography, a variety of aperture-based near-field probes can be fabricated with high optical performance. In particular, the combination of large transmission through a C-shaped aperture aligned to the sharp apex (<10 nm radius) of a template-stripped metallic pyramid allows the efficient delivery of light--via the C-shaped aperture--while providing a nanometric hotspot determined by the sharpness of the tip itself.
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Sampling and energy evaluation challenges in ligand binding protein design.
Dou, Jiayi; Doyle, Lindsey; Jr Greisen, Per; Schena, Alberto; Park, Hahnbeom; Johnsson, Kai; Stoddard, Barry L; Baker, David
2017-12-01
The steroid hormone 17α-hydroxylprogesterone (17-OHP) is a biomarker for congenital adrenal hyperplasia and hence there is considerable interest in development of sensors for this compound. We used computational protein design to generate protein models with binding sites for 17-OHP containing an extended, nonpolar, shape-complementary binding pocket for the four-ring core of the compound, and hydrogen bonding residues at the base of the pocket to interact with carbonyl and hydroxyl groups at the more polar end of the ligand. Eight of 16 designed proteins experimentally tested bind 17-OHP with micromolar affinity. A co-crystal structure of one of the designs revealed that 17-OHP is rotated 180° around a pseudo-two-fold axis in the compound and displays multiple binding modes within the pocket, while still interacting with all of the designed residues in the engineered site. Subsequent rounds of mutagenesis and binding selection improved the ligand affinity to nanomolar range, while appearing to constrain the ligand to a single bound conformation that maintains the same "flipped" orientation relative to the original design. We trace the discrepancy in the design calculations to two sources: first, a failure to model subtle backbone changes which alter the distribution of sidechain rotameric states and second, an underestimation of the energetic cost of desolvating the carbonyl and hydroxyl groups of the ligand. The difference between design model and crystal structure thus arises from both sampling limitations and energy function inaccuracies that are exacerbated by the near two-fold symmetry of the molecule. © 2017 The Authors Protein Science published by Wiley Periodicals, Inc. on behalf of The Protein Society.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Xue, Teng; Lin, Zhaoyang; Chiu, Chin-Yi
Metallic nanoparticles are emerging as an exciting class of heterogeneous catalysts with the potential advantages of exceptional activity, stability, recyclability, and easier separation than homogeneous catalysts. The traditional colloid nanoparticle syntheses usually involve strong surface binding ligands that could passivate the surface active sites and result in poor catalytic activity. The subsequent removal of surface ligands could reactivate the surface but often leads to metal ion leaching and/or severe Ostwald ripening with diminished catalytic activity or poor stability. Molecular ligand engineering represents a powerful strategy for the design of homogeneous molecular catalysts but is insufficiently explored for nanoparticle catalysts tomore » date. We report a systematic investigation on molecular ligand modulation of palladium (Pd) nanoparticle catalysts. Our studies show that β-functional groups of butyric acid ligand on Pd nanoparticles can significantly modulate the catalytic reaction process to modify the catalytic activity and stability for important aerobic reactions. With a β-hydroxybutyric acid ligand, the Pd nanoparticle catalysts exhibit exceptional catalytic activity and stability with an unsaturated turnover number (TON) >3000 for dehydrogenative oxidation of cyclohexenone to phenol, greatly exceeding that of homogeneous Pd(II) catalysts (TON, ~30). This study presents a systematic investigation of molecular ligand modulation of nanoparticle catalysts and could open up a new pathway toward the design and construction of highly efficient and robust heterogeneous catalysts through molecular ligand engineering.« less
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Ghosh, Arun K; R Nyalapatla, Prasanth; Kovela, Satish; Rao, Kalapala Venkateswara; Brindisi, Margherita; Osswald, Heather L; Amano, Masayuki; Aoki, Manabu; Agniswamy, Johnson; Wang, Yuan-Fang; Weber, Irene T; Mitsuya, Hiroaki
2018-05-24
The design, synthesis, and biological evaluation of a new class of HIV-1 protease inhibitors containing stereochemically defined fused tricyclic polyethers as the P2 ligands and a variety of sulfonamide derivatives as the P2' ligands are described. A number of ring sizes and various substituent effects were investigated to enhance the ligand-backbone interactions in the protease active site. Inhibitors 5c and 5d containing this unprecedented fused 6-5-5 ring system as the P2 ligand, an aminobenzothiazole as the P2' ligand, and a difluorophenylmethyl as the P1 ligand exhibited exceptional enzyme inhibitory potency and maintained excellent antiviral activity against a panel of highly multidrug-resistant HIV-1 variants. The umbrella-like P2 ligand for these inhibitors has been synthesized efficiently in an optically active form using a Pauson-Khand cyclization reaction as the key step. The racemic alcohols were resolved efficiently using a lipase catalyzed enzymatic resolution. Two high resolution X-ray structures of inhibitor-bound HIV-1 protease revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insight into the binding properties of these new inhibitors.
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Outcome of the First wwPDB/CCDC/D3R Ligand Validation Workshop
DOE Office of Scientific and Technical Information (OSTI.GOV)
Adams, Paul D.; Aertgeerts, Kathleen; Bauer, Cary
Crystallographic studies of ligands bound to biological macromolecules (proteins and nucleic acids) represent an important source of information concerning drug-target interactions, providing atomic level insights into the physical chemistry of complex formation between macromolecules and ligands. Of the more than 115,000 entries extant in the Protein Data Bank archive, ~75% include at least one non-polymeric ligand. Ligand geometrical and stereochemical quality, the suitability of ligand models for in silico drug discovery/design, and the goodness-of-fit of ligand models to electron density maps vary widely across the archive. We describe the proceedings and conclusions from the first Worldwide Protein Data Bank/Cambridge Crystallographicmore » Data Centre/Drug Design Data Resource (wwPDB/CCDC/D3R) Ligand Validation Workshop held at the Research Collaboratory for Structural Bioinformatics at Rutgers University on July 30-31, 2015. Experts in protein crystallography from academe and industry came together with non-profit and for-profit software providers for crystallography and with experts in computational chemistry and data archiving to discuss and make recommendations on best practices, as framed by a series of questions central to structural studies of macromolecule-ligand complexes. What data concerning bound ligands should be archived in the Protein Data Bank? How should the ligands be best represented? How should structural models of macromolecule-ligand complexes be validated? What supplementary information should accompany publications of structural studies of biological macromolecules? Consensus recommendations on best practices developed in response to each of these questions are provided, together with some details regarding implementation. Important issues addressed but not resolved at the workshop are also enumerated.« less
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Outcome of the First wwPDB/CCDC/D3R Ligand Validation Workshop
Adams, Paul D.; Aertgeerts, Kathleen; Bauer, Cary; ...
2016-04-05
Crystallographic studies of ligands bound to biological macromolecules (proteins and nucleic acids) represent an important source of information concerning drug-target interactions, providing atomic level insights into the physical chemistry of complex formation between macromolecules and ligands. Of the more than 115,000 entries extant in the Protein Data Bank archive, ~75% include at least one non-polymeric ligand. Ligand geometrical and stereochemical quality, the suitability of ligand models for in silico drug discovery/design, and the goodness-of-fit of ligand models to electron density maps vary widely across the archive. We describe the proceedings and conclusions from the first Worldwide Protein Data Bank/Cambridge Crystallographicmore » Data Centre/Drug Design Data Resource (wwPDB/CCDC/D3R) Ligand Validation Workshop held at the Research Collaboratory for Structural Bioinformatics at Rutgers University on July 30-31, 2015. Experts in protein crystallography from academe and industry came together with non-profit and for-profit software providers for crystallography and with experts in computational chemistry and data archiving to discuss and make recommendations on best practices, as framed by a series of questions central to structural studies of macromolecule-ligand complexes. What data concerning bound ligands should be archived in the Protein Data Bank? How should the ligands be best represented? How should structural models of macromolecule-ligand complexes be validated? What supplementary information should accompany publications of structural studies of biological macromolecules? Consensus recommendations on best practices developed in response to each of these questions are provided, together with some details regarding implementation. Important issues addressed but not resolved at the workshop are also enumerated.« less
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Outcome of the First wwPDB/CCDC/D3R Ligand Validation Workshop.
Adams, Paul D; Aertgeerts, Kathleen; Bauer, Cary; Bell, Jeffrey A; Berman, Helen M; Bhat, Talapady N; Blaney, Jeff M; Bolton, Evan; Bricogne, Gerard; Brown, David; Burley, Stephen K; Case, David A; Clark, Kirk L; Darden, Tom; Emsley, Paul; Feher, Victoria A; Feng, Zukang; Groom, Colin R; Harris, Seth F; Hendle, Jorg; Holder, Thomas; Joachimiak, Andrzej; Kleywegt, Gerard J; Krojer, Tobias; Marcotrigiano, Joseph; Mark, Alan E; Markley, John L; Miller, Matthew; Minor, Wladek; Montelione, Gaetano T; Murshudov, Garib; Nakagawa, Atsushi; Nakamura, Haruki; Nicholls, Anthony; Nicklaus, Marc; Nolte, Robert T; Padyana, Anil K; Peishoff, Catherine E; Pieniazek, Susan; Read, Randy J; Shao, Chenghua; Sheriff, Steven; Smart, Oliver; Soisson, Stephen; Spurlino, John; Stouch, Terry; Svobodova, Radka; Tempel, Wolfram; Terwilliger, Thomas C; Tronrud, Dale; Velankar, Sameer; Ward, Suzanna C; Warren, Gregory L; Westbrook, John D; Williams, Pamela; Yang, Huanwang; Young, Jasmine
2016-04-05
Crystallographic studies of ligands bound to biological macromolecules (proteins and nucleic acids) represent an important source of information concerning drug-target interactions, providing atomic level insights into the physical chemistry of complex formation between macromolecules and ligands. Of the more than 115,000 entries extant in the Protein Data Bank (PDB) archive, ∼75% include at least one non-polymeric ligand. Ligand geometrical and stereochemical quality, the suitability of ligand models for in silico drug discovery and design, and the goodness-of-fit of ligand models to electron-density maps vary widely across the archive. We describe the proceedings and conclusions from the first Worldwide PDB/Cambridge Crystallographic Data Center/Drug Design Data Resource (wwPDB/CCDC/D3R) Ligand Validation Workshop held at the Research Collaboratory for Structural Bioinformatics at Rutgers University on July 30-31, 2015. Experts in protein crystallography from academe and industry came together with non-profit and for-profit software providers for crystallography and with experts in computational chemistry and data archiving to discuss and make recommendations on best practices, as framed by a series of questions central to structural studies of macromolecule-ligand complexes. What data concerning bound ligands should be archived in the PDB? How should the ligands be best represented? How should structural models of macromolecule-ligand complexes be validated? What supplementary information should accompany publications of structural studies of biological macromolecules? Consensus recommendations on best practices developed in response to each of these questions are provided, together with some details regarding implementation. Important issues addressed but not resolved at the workshop are also enumerated. Copyright © 2016 Elsevier Ltd. All rights reserved.
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Outcome of the first wwPDB/CCDC/D3R Ligand Validation Workshop
Adams, Paul D.; Aertgeerts, Kathleen; Bauer, Cary; Bell, Jeffrey A.; Berman, Helen M.; Bhat, Talapady N.; Blaney, Jeff; Bolton, Evan; Bricogne, Gerard; Brown, David; Burley, Stephen K.; Case, David A.; Clark, Kirk L.; Darden, Tom; Emsley, Paul; Feher, Victoria A.; Feng, Zukang; Groom, Colin R.; Harris, Seth F.; Hendle, Jorg; Holder, Thomas; Joachimiak, Andrzej; Kleywegt, Gerard J.; Krojer, Tobias; Marcotrigiano, Joseph; Mark, Alan E.; Markley, John L.; Miller, Matthew; Minor, Wladek; Montelione, Gaetano T.; Murshudov, Garib; Nakagawa, Atsushi; Nakamura, Haruki; Nicholls, Anthony; Nicklaus, Marc; Nolte, Robert T.; Padyana, Anil K.; Peishoff, Catherine E.; Pieniazek, Susan; Read, Randy J.; Shao, Chenghua; Sheriff, Steven; Smart, Oliver; Soisson, Stephen; Spurlino, John; Stouch, Terry; Svobodova, Radka; Tempel, Wolfram; Terwilliger, Thomas C.; Tronrud, Dale; Velankar, Sameer; Ward, Suzanna; Warren, Gregory L.; Westbrook, John D.; Williams, Pamela; Yang, Huanwang; Young, Jasmine
2016-01-01
Summary Crystallographic studies of ligands bound to biological macromolecules (proteins and nucleic acids) represent an important source of information concerning drug-target interactions, providing atomic level insights into the physical chemistry of complex formation between macromolecules and ligands. Of the more than 115,000 entries extant in the Protein Data Bank archive, ~75% include at least one non-polymeric ligand. Ligand geometrical and stereochemical quality, the suitability of ligand models for in silico drug discovery/design, and the goodness-of-fit of ligand models to electron density maps vary widely across the archive. We describe the proceedings and conclusions from the first Worldwide Protein Data Bank/Cambridge Crystallographic Data Centre/Drug Design Data Resource (wwPDB/CCDC/D3R) Ligand Validation Workshop held at the Research Collaboratory for Structural Bioinformatics at Rutgers University on July 30–31, 2015. Experts in protein crystallography from academe and industry came together with non-profit and for-profit software providers for crystallography and with experts in computational chemistry and data archiving to discuss and make recommendations on best practices, as framed by a series of questions central to structural studies of macromolecule-ligand complexes. What data concerning bound ligands should be archived in the Protein Data Bank? How should the ligands be best represented? How should structural models of macromolecule-ligand complexes be validated? What supplementary information should accompany publications of structural studies of biological macromolecules? Consensus recommendations on best practices developed in response to each of these questions are provided, together with some details regarding implementation. Important issues addressed but not resolved at the workshop are also enumerated. PMID:27050687
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Structural determinants for the inhibitory ligands of orotidine-5′-monophosphate decarboxylase
DOE Office of Scientific and Technical Information (OSTI.GOV)
Meza-Avina, Maria Elena; Wei, Lianhu; Liu, Yan
2010-06-14
In recent years, orotidine-5{prime}-monophosphate decarboxylase (ODCase) has gained renewed attention as a drug target. As a part of continuing efforts to design novel inhibitors of ODCase, we undertook a comprehensive study of potent, structurally diverse ligands of ODCase and analyzed their structural interactions in the active site of ODCase. These ligands comprise of pyrazole or pyrimidine nucleotides including the mononucleotide derivatives of pyrazofurin, barbiturate ribonucleoside, and 5-cyanouridine, as well as, in a computational approach, 1,4-dihydropyridine-based non-nucleoside inhibitors such as nifedipine and nimodipine. All these ligands bind in the active site of ODCase exhibiting distinct interactions paving the way to designmore » novel inhibitors against this interesting enzyme. We propose an empirical model for the ligand structure for rational modifications in new drug design and potentially new lead structures.« less
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Simple and fast screening of G-quadruplex ligands with electrochemical detection system.
Fan, Qiongxuan; Li, Chao; Tao, Yaqin; Mao, Xiaoxia; Li, Genxi
2016-11-01
Small molecules that may facilitate and stabilize the formation of G-quadruplexes can be used for cancer treatments, because the G-quadruplex structure can inhibit the activity of telomerase, an enzyme over-expressed in many cancer cells. Therefore, there is considerable interest in developing a simple and high-performance method for screening small molecules binding to G-quadruplex. Here, we have designed a simple electrochemical approach to screen such ligands based on the fact that the formation and stabilization of G-quadruplex by ligand may inhibit electron transfer of redox species to electrode surface. As a proof-of-concept study, two types of classical G-quadruplex ligands, TMPyP4 and BRACO-19, are studied in this work, which demonstrates that this method is fast and robust and it may be applied to screen G-quadruplex ligands for anticancer drugs testing and design in the future. Copyright © 2016 Elsevier B.V. All rights reserved.
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Rational Ligand Design for U(VI) and Pu(IV)
DOE Office of Scientific and Technical Information (OSTI.GOV)
Szigethy, Geza
2009-08-12
Nuclear power is an attractive alternative to hydrocarbon-based energy production at a time when moving away from carbon-producing processes is widely accepted as a significant developmental need. Hence, the radioactive actinide power sources for this industry are necessarily becoming more widespread, which is accompanied by the increased risk of exposure to both biological and environmental systems. This, in turn, requires the development of technology designed to remove such radioactive threats efficiently and selectively from contaminated material, whether that be contained nuclear waste streams or the human body. Raymond and coworkers (University of California, Berkeley) have for decades investigated the interactionmore » of biologically-inspired, hard Lewis-base ligands with high-valent, early-actinide cations. It has been established that such ligands bind strongly to the hard Lewis-acidic early actinides, and many poly-bidentate ligands have been developed and shown to be effective chelators of actinide contaminants in vivo. Work reported herein explores the effect of ligand geometry on the linear U(IV) dioxo dication (uranyl, UO 2 2+). The goal is to utilize rational ligand design to develop ligands that exhibit shape selectivity towards linear dioxo cations and provides thermodynamically favorable binding interactions. The uranyl complexes with a series of tetradentate 3-hydroxy-pyridin-2-one (3,2-HOPO) ligands were studied in both the crystalline state as well as in solution. Despite significant geometric differences, the uranyl affinities of these ligands vary only slightly but are better than DTPA, the only FDA-approved chelation therapy for actinide contamination. The terepthalamide (TAM) moiety was combined into tris-beidentate ligands with 1,2- and 3,2-HOPO moieties were combined into hexadentate ligands whose structural preferences and solution thermodynamics were measured with the uranyl cation. In addition to achieving coordinative saturation, these ligands exhibited increased uranyl affinity compared to bis-Me-3,2-HOPO ligands. This result is due in part to their increased denticity, but is primarily the result of the presence of the TAM moiety. In an effort to explore the relatively unexplored coordination chemistry of Pu(IV) with bidentate moieties, a series of Pu(IV) complexes were also crystallized using bidentate hydroxypyridinone and hydroxypyrone ligands. The geometries of these complexes are compared to that of the analogous Ce(IV) complexes. While in some cases these showed the expected structural similarities, some ligand systems led to significant coordination changes. A series of crystal structure analyses with Ce(IV) indicated that these differences are most likely the result of crystallization condition differences and solvent inclusion effects.« less
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Development of Liver-Targeting Insulin
2017-08-01
decision unless so designated by other documentation. REPORT DOCUMENTATION PAGE Form Approved OMB No. 0704-0188 Public reporting burden for this...have been done in the design of better insulin, problems still exist with the current therapies. For example, frequent subcutaneous injections are always...ligands will be designed and synthesized. The ligands molecular weight is a fraction of insulin, and therefore should result in an insulin analog with
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Palencia, Andrés; Cobos, Eva S; Mateo, Pedro L; Martínez, Jose C; Luque, Irene
2004-02-13
The inhibition of the interactions between SH3 domains and their targets is emerging as a promising therapeutic strategy. To date, rational design of potent ligands for these domains has been hindered by the lack of understanding of the origins of the binding energy. We present here a complete thermodynamic analysis of the binding energetics of the p41 proline-rich decapeptide (APSYSPPPPP) to the SH3 domain of the c-Abl oncogene. Isothermal titration calorimetry experiments have revealed a thermodynamic signature for this interaction (very favourable enthalpic contributions opposed by an unfavourable binding entropy) inconsistent with the highly hydrophobic nature of the p41 ligand and the Abl-SH3 binding site. Our structural and thermodynamic analyses have led us to the conclusion, having once ruled out any possible ionization events or conformational changes coupled to the association, that the establishment of a complex hydrogen-bond network mediated by water molecules buried at the binding interface is responsible for the observed thermodynamic behaviour. The origin of the binding energetics for proline-rich ligands to the Abl-SH3 domain is further investigated by a comparative calorimetric analysis of a set of p41-related ligands. The striking effects upon the enthalpic and entropic contributions provoked by conservative substitutions at solvent-exposed positions in the ligand confirm the complexity of the interaction. The implications of these results for rational ligand design are discussed.
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Computational Design of Metal Ion Sequestering Agents
DOE Office of Scientific and Technical Information (OSTI.GOV)
Hay, Benjamin P.; Rapko, Brian M.
Organic ligands that exhibit a high degree of metal ion recognition are essential precursors for developing separation processes and sensors for metal ions. Since the beginning of the nuclear era, much research has focused on discovering ligands that target specific radionuclides. Members of the Group 1A and 2A cations (e.g., Cs, Sr, Ra) and the f-block metals (actinides and lanthanides) are of primary concern to DOE. Although there has been some success in identifying ligand architectures that exhibit a degree of metal ion recognition, the ability to control binding affinity and selectivity remains a significant challenge. The traditional approach formore » discovering such ligands has involved lengthy programs of organic synthesis and testing that, in the absence of reliable methods for screening compounds before synthesis, have resulted in much wasted research effort. This project seeks to enhance and strengthen the traditional approach through computer-aided design of new and improved host molecules. Accurate electronic structure calculations are coupled with experimental data to provide fundamental information about ligand structure and the nature of metal-donor group interactions (design criteria). This fundamental information then is used in a molecular mechanics model (MM) that helps us rapidly screen proposed ligand architectures and select the best members from a set of potential candidates. By using combinatorial methods, molecule building software has been developed that generates large numbers of candidate architectures for a given set of donor groups. The specific goals of this project are: • further understand the structural and energetic aspects of individual donor group- metal ion interactions and incorporate this information within the MM framework • further develop and evaluate approaches for correlating ligand structure with reactivity toward metal ions, in other words, screening capability • use molecule structure building software to generate large numbers of candidate ligand architectures for given sets of donor groups • screen candidates and identify ligand architectures that will exhibit enhanced metal ion recognition. These new capabilities are being applied to ligand systems identified under other DOEsponsored projects where studies have suggested that modifying existing architectures will lead to dramatic enhancements in metal ion binding affinity and selectivity. With this in mind, we are collaborating with Professors R. T. Paine (University of New Mexico), K. N. Raymond (University of California, Berkeley), and J. E. Hutchison (University of Oregon), and Dr. B. A. Moyer (Oak Ridge National Laboratory) to obtain experimental validation of the predicted new ligand structures. Successful completion of this study will yield molecular-level insight into the role that ligand architecture plays in controlling metal ion complexation and will provide a computational approach to ligand design.« less
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ERIC Educational Resources Information Center
Pennington, Robert; Koehler, Mallory
2017-01-01
There is limited research on teaching narrative writing skills to students with moderate to severe intellectual disability. In the current study, we used a multiple probe across participants single case design to evaluate the effects of an intervention package comprised of modeling, story templates, and self-graphing, on the inclusion of story…
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Gonzalez, J; Marchand-Geneste, N; Giraudel, J L; Shimada, T
2012-01-01
To obtain chemical clues on the process of bioactivation by cytochromes P450 1A1 and 1B1, some QSAR studies were carried out based on cellular experiments of the metabolic activation of polycyclic aromatic hydrocarbons and heterocyclic aromatic compounds by those enzymes. Firstly, the 3D structures of cytochromes 1A1 and 1B1 were built using homology modelling with a cytochrome 1A2 template. Using these structures, 32 ligands including heterocyclic aromatic compounds, polycyclic aromatic hydrocarbons and corresponding diols, were docked with LigandFit and CDOCKER algorithms. Binding mode analysis highlighted the importance of hydrophobic interactions and the hydrogen bonding network between cytochrome amino acids and docked molecules. Finally, for each enzyme, multilinear regression and artificial neural network QSAR models were developed and compared. These statistical models highlighted the importance of electronic, structural and energetic descriptors in metabolic activation process, and could be used for virtual screening of ligand databases. In the case of P450 1A1, the best model was obtained with artificial neural network analysis and gave an r (2) of 0.66 and an external prediction [Formula: see text] of 0.73. Concerning P450 1B1, artificial neural network analysis gave a much more robust model, associated with an r (2) value of 0.73 and an external prediction [Formula: see text] of 0.59.
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Phenanthridine-Containing Pincer-like Amido Complexes of Nickel, Palladium, and Platinum.
Mandapati, Pavan; Giesbrecht, Patrick K; Davis, Rebecca L; Herbert, David E
2017-03-20
Proligands based on bis(8-quinolinyl)amine (L1) were prepared containing one (L2) and two (L3) benzo-fused N-heterocyclic phenanthridinyl (3,4-benzoquinolinyl) units. Taken as a series, L1-L3 provides a ligand template for exploring systematic π-extension in the context of tridentate pincer-like amido complexes of group 10 metals (1-M, 2-M, and 3-M; M = Ni, Pd, Pt). Inclusion of phenanthridinyl units was enabled by development of a cross-coupling/condensation route to 6-unsubstituted, 4-substituted phenanthridines (4-Br, 4-NO 2 , 4-NH 2 ) suitable for elaboration into the target ligand frameworks. Complexes 1-M, 2-M, and 3-M are redox-active; electrochemistry and UV-vis absorption spectroscopy were used to investigate the impact of π-extension on the electronic properties of the metal complexes. Unlike what is typically observed for benzannulated ligand-metal complexes, extending the π-system in metal complexes 1-M to 2-M to 3-M led to only a moderate red shift in the relative highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) gap as estimated by electrochemistry and similarly subtle changes to the onset of the lowest-energy absorption observed by UV-vis spectroscopy. Time-dependent density functional theory calculations revealed that benzannulation significantly impacts the atomic contributions to the LUMO and LUMO+1 orbitals, altering the orbital contributions to the lowest-energy transition but leaving the energy of this transition essentially unchanged.
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Liu, Zhenyu; Szarecka, Agnieszka; Yonkunas, Michael; Speranskiy, Kirill; Kurnikova, Maria; Cascio, Michael
2014-01-01
The glycine receptor (GlyR), a member of the pentameric ligand-gated ion channel superfamily, is the major inhibitory neurotransmitter-gated receptor in the spinal cord and brainstem. In these receptors, the extracellular domain binds agonists, antagonists and various other modulatory ligands that act allosterically to modulate receptor function. The structures of homologous receptors and binding proteins provide templates for modeling of the ligand-binding domain of GlyR, but limitations in sequence homology and structure resolution impact on modeling studies. The determination of distance constraints via chemical crosslinking studies coupled with mass spectrometry can provide additional structural information to aid in model refinement, however it is critical to be able to distinguish between intra- and inter-subunit constraints. In this report we model the structure of GlyBP, a structural and functional homolog of the extracellular domain of human homomeric α1 GlyR. We then show that intra- and intersubunit Lys-Lys crosslinks in trypsinized samples of purified monomeric and oligomeric protein bands from SDS-polyacrylamide gels may be identified and differentiated by MALDI-TOF MS studies of limited resolution. Thus, broadly available MS platforms are capable of providing distance constraints that may be utilized in characterizing large complexes that may be less amenable to NMR and crystallographic studies. Systematic studies of state-dependent chemical crosslinking and mass spectrometric identification of crosslinked sites has the potential to complement computational modeling efforts by providing constraints that can validate and refine allosteric models. PMID:25025226
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Tapiero-Rodriguez, Sandra M; Acosta Guio, Johanna C; Porras-Hurtado, Gloria Liliana; García, Natalia; Solano, Martha; Pachajoa, Harry; Velasco, Harvy M
2018-01-01
Background As mucopolysaccharidosis IVA (MPS IVA) is the most frequent MPS in Colombia, this paper aims to describe its clinical and mutational characteristics in 32 diagnosed patients included in this study. Methods Genotyping was completed by amplification and Sanger sequencing of the GALNS gene. The SWISS-model platform was used for bioinformatic analysis, and mutant proteins were generated by homology from the wild-type GALNS code 4FDI template from the Protein Data Bank (PDB) database. Docking was performed using the GalNAc6S ligand (PubChem CID: 193456) by AutoDock Vina 1.0 and visualized in PyMOL and LigPlot+. Results Eleven variants were identified, and one new pathogenic variant was described in the heterozygous state, which is consistent with genotype c. 319 G> T or p.Ala107Ser. The pathogenic variant c.901G>T or p.Gly301Cys was the most frequent mutation with 51.6% of alleles. Docking revealed affinity energy of −5.9 Kcal/mol between wild-type GALNS and the G6S ligand. Some changes were evidenced at the intermolecular interaction level, and affinity energy for each mutant decreased. Conclusion Clinical variables and genotypic analysis were similar to those reported for other world populations. Genotypic data showed greater allelic heterogeneity than those previously reported. Bioinformatics tools showed differences in the binding interactions of mutant proteins with the G6S ligand, in regard the wild-type GALNS. PMID:29731656
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Porous titanium scaffolds fabricated using a rapid prototyping and powder metallurgy technique.
Ryan, Garrett E; Pandit, Abhay S; Apatsidis, Dimitrios P
2008-09-01
One of the main issues in orthopaedic implant design is the fabrication of scaffolds that closely mimic the biomechanical properties of the surrounding bone. This research reports on a multi-stage rapid prototyping technique that was successfully developed to produce porous titanium scaffolds with fully interconnected pore networks and reproducible porosity and pore size. The scaffolds' porous characteristics were governed by a sacrificial wax template, fabricated using a commercial 3D-printer. Powder metallurgy processes were employed to generate the titanium scaffolds by filling around the wax template with titanium slurry. In the attempt to optimise the powder metallurgy technique, variations in slurry concentration, compaction pressure and sintering temperature were investigated. By altering the wax design template, pore sizes ranging from 200 to 400 microm were achieved. Scaffolds with porosities of 66.8 +/- 3.6% revealed compression strengths of 104.4+/-22.5 MPa in the axial direction and 23.5 +/- 9.6 MPa in the transverse direction demonstrating their anisotropic nature. Scaffold topography was characterised using scanning electron microscopy and microcomputed tomography. Three-dimensional reconstruction enabled the main architectural parameters such as pore size, interconnecting porosity, level of anisotropy and level of structural disorder to be determined. The titanium scaffolds were compared to their intended designs, as governed by their sacrificial wax templates. Although discrepancies in architectural parameters existed between the intended and the actual scaffolds, overall the results indicate that the porous titanium scaffolds have the properties to be potentially employed in orthopaedic applications.
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Walter, William R; Goldberg-Stein, Shlomit; Levsky, Jeffrey M; Cohen, Hillel W; Scheinfeld, Meir H
2015-08-01
The aim of this study was to compare the accuracy of coronary atherosclerosis reporting before and after the implementation of a structured reporting chest CT template. A noncardiac, noncontrast chest CT structured reporting template was developed and mandated for department-wide use at a large academic center. The template included the statement "There are no coronary artery calcifications." All noncardiac, noncontrast chest CT examinations reported over 3 days, 1 month after template implementation (structured template group), and from a 3-day period 1 year prior (control group) were retrospectively collected. Final radiology reports were reviewed and designated positive or negative for coronary calcifications. CT images were reviewed in consensus by 2 radiologists, who scored each case for the presence or absence of coronary calcifications, blinded to the original report. Statistical analysis was performed using Pearson χ(2) and Fisher exact tests. Sixty-five percent (69 of 106) of structured template group and 58% (62 of 106) of control group cases had coronary calcifications. Reports from the structured template group were more likely to correctly state the presence or absence of coronary atherosclerosis compared with those from the control group (96.2% vs 85.8%; odds ratio, 4.2; 95% confidence interval, 1.3-13.1; P = .008). Structured template group reports were less likely to be falsely negative compared with control group reports (3.8% vs 11.7%; odds ratio, 3.4; 95% confidence interval, 1.0-10.8; P = .03). Implementing a structured reporting template improves reporting accuracy of coronary calcifications. Copyright © 2015 American College of Radiology. Published by Elsevier Inc. All rights reserved.
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Tan, Yaw Sing; Spring, David R; Abell, Chris; Verma, Chandra S
2015-07-14
A computational ligand-mapping approach to detect protein surface pockets that interact with hydrophobic moieties is presented. In this method, we incorporated benzene molecules into explicit solvent molecular dynamics simulations of various protein targets. The benzene molecules successfully identified the binding locations of hydrophobic hot-spot residues and all-hydrocarbon cross-links from known peptidic ligands. They also unveiled cryptic binding sites that are occluded by side chains and the protein backbone. Our results demonstrate that ligand-mapping molecular dynamics simulations hold immense promise to guide the rational design of peptidic modulators of protein-protein interactions, including that of stapled peptides, which show promise as an exciting new class of cell-penetrating therapeutic molecules.
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Khashan, Raed S
2015-01-01
As the number of available ligand-receptor complexes is increasing, researchers are becoming more dedicated to mine these complexes to aid in the drug design and development process. We present free software which is developed as a tool for performing similarity search across ligand-receptor complexes for identifying binding pockets which are similar to that of a target receptor. The search is based on 3D-geometric and chemical similarity of the atoms forming the binding pocket. For each match identified, the ligand's fragment(s) corresponding to that binding pocket are extracted, thus forming a virtual library of fragments (FragVLib) that is useful for structure-based drug design. The program provides a very useful tool to explore available databases.
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Development of immobilized ligands for actinide separations. Final report, June 1991--May 1994
DOE Office of Scientific and Technical Information (OSTI.GOV)
Paine, R.T.
1994-06-01
Primary goals during this grant period were to (1) synthesize new bifunctional chelating ligands, (2) characterize the structural features of the Ln and An coordination complexes formed by these ligands, (3) use structural data to iteratively design new classes of multifunctional ligands, and (4) explore additional routes for attachment of key ligands to solid supports that could be useful for chromatographic separations. Some highlights of recently published work as well as a summary of submitted, unpublished and/or still in progress research are outlined.
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Schilling, Mauro; Böhler, Michael; Luber, Sandra
2018-05-21
In order to rationally design water oxidation catalysts (WOCs), an in-depth understanding of the reaction mechanism is essential. In this study we showcase the complexity of catalytic water oxidation, by elucidating how modifications of the pentapyridyl (Py5) ligand-framework influence the thermodynamics and kinetics of the process. In the reaction mechanism the pyridine-water exchange was identified as a key reaction which appears to determine the reactivity of the Py5-WOCs. Exploring the capabilities of in silico design we show which modifications of the ligand framework appear promising when attempting to improve the catalytic performance of WOCs derived from Py5.
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Raman, E Prabhu; Lakkaraju, Sirish Kaushik; Denny, Rajiah Aldrin; MacKerell, Alexander D
2017-06-05
Accurate and rapid estimation of relative binding affinities of ligand-protein complexes is a requirement of computational methods for their effective use in rational ligand design. Of the approaches commonly used, free energy perturbation (FEP) methods are considered one of the most accurate, although they require significant computational resources. Accordingly, it is desirable to have alternative methods of similar accuracy but greater computational efficiency to facilitate ligand design. In the present study relative free energies of binding are estimated for one or two non-hydrogen atom changes in compounds targeting the proteins ACK1 and p38 MAP kinase using three methods. The methods include standard FEP, single-step free energy perturbation (SSFEP) and the site-identification by ligand competitive saturation (SILCS) ligand grid free energy (LGFE) approach. Results show the SSFEP and SILCS LGFE methods to be competitive with or better than the FEP results for the studied systems, with SILCS LGFE giving the best agreement with experimental results. This is supported by additional comparisons with published FEP data on p38 MAP kinase inhibitors. While both the SSFEP and SILCS LGFE approaches require a significant upfront computational investment, they offer a 1000-fold computational savings over FEP for calculating the relative affinities of ligand modifications once those pre-computations are complete. An illustrative example of the potential application of these methods in the context of screening large numbers of transformations is presented. Thus, the SSFEP and SILCS LGFE approaches represent viable alternatives for actively driving ligand design during drug discovery and development. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.
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NASA Astrophysics Data System (ADS)
So, Sung-Sau; Karplus, Martin
2001-07-01
Glycogen phosphorylase (GP) is an important enzyme that regulates blood glucose level and a key therapeutic target for the treatment of type II diabetes. In this study, a number of potential GP inhibitors are designed with a variety of computational approaches. They include the applications of MCSS, LUDI and CoMFA to identify additional fragments that can be attached to existing lead molecules; the use of 2D and 3D similarity-based QSAR models (HQSAR and SMGNN) and of the LUDI program to identify novel molecules that may bind to the glucose binding site. The designed ligands are evaluated by a multiple screening method, which is a combination of commercial and in-house ligand-receptor binding affinity prediction programs used in a previous study (So and Karplus, J. Comp.-Aid. Mol. Des., 13 (1999), 243-258). Each method is used at an appropriate point in the screening, as determined by both the accuracy of the calculations and the computational cost. A comparison of the strengths and weaknesses of the ligand design approaches is made.
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Cassetta, M; Giansanti, M
2016-07-01
A reduction in orthodontic treatment time can be attained using corticotomies. The aggressive nature of corticotomy due to the elevation of muco-periosteal flaps and to the duration of the surgery raised reluctance for its employ among patients and dental community. This study aims to provide detailed information on the design and manufacture of a 3D-printed CAD-CAM (computer-aided design and computer-aided manufacturing) surgical guide which can aid the clinician in achieving a minimally-invasive, flapless corticotomy. An impression of dental arches was created; the models were digitally-acquired using a 3D scanner and saved as STereoLithography ( STL ) files. The patient underwent cone beam computed tomography (CBCT): images of jaws and teeth were transformed into 3D models and saved as an STL file. An acrylic template with the design of a surgical guide was manufactured and scanned. The STLs of jaws, scanned casts, and acrylic templates were matched. 3D modeling software allowed the view of the 3D models from different perspectives and planes with perfect rendering. The 3D model of the acrylic template was transformed into a surgical guide with slots designed to guide, at first, a scalpel blade and then a piezoelectric cutting insert. The 3D STL model of the surgical guide was printed. This procedure allowed the manufacturing of a 3D-printed CAD/CAM surgical guide, which overcomes the disadvantages of the corticotomy, removing the need for flap elevation. No discomfort, early surgical complications or unexpected events were observed. The effectiveness of this minimally-invasive surgical technique can offer the clinician a valid alternative to other methods currently in use.
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Wauters, Lauri D J; Miguel-Moragas, Joan San; Mommaerts, Maurice Y
2015-11-01
To gain insight into the methodology of different computer-aided design-computer-aided manufacturing (CAD-CAM) applications for the reconstruction of cranio-maxillo-facial (CMF) defects. We reviewed and analyzed the available literature pertaining to CAD-CAM for use in CMF reconstruction. We proposed a classification system of the techniques of implant and cutting, drilling, and/or guiding template design and manufacturing. The system consisted of 4 classes (I-IV). These classes combine techniques used for both the implant and template to most accurately describe the methodology used. Our classification system can be widely applied. It should facilitate communication and immediate understanding of the methodology of CAD-CAM applications for the reconstruction of CMF defects.
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Russo, Simonetta; Callegari, Donatella; Incerti, Matteo; Pala, Daniele; Giorgio, Carmine; Brunetti, Jlenia; Bracci, Luisa; Vicini, Paola; Barocelli, Elisabetta; Capoferri, Luigi; Rivara, Silvia; Tognolini, Massimiliano; Mor, Marco; Lodola, Alessio
2016-06-06
The free-energy surface (FES) of protein-ligand binding contains information useful for drug design. Here we show how to exploit a free-energy minimum of a protein-ligand complex identified by metadynamics simulations to design a new EphA2 antagonist with improved inhibitory potency. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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Identifying Drug-Target Interactions with Decision Templates.
Yan, Xiao-Ying; Zhang, Shao-Wu
2018-01-01
During the development process of new drugs, identification of the drug-target interactions wins primary concerns. However, the chemical or biological experiments bear the limitation in coverage as well as the huge cost of both time and money. Based on drug similarity and target similarity, chemogenomic methods can be able to predict potential drug-target interactions (DTIs) on a large scale and have no luxurious need about target structures or ligand entries. In order to reflect the cases that the drugs having variant structures interact with common targets and the targets having dissimilar sequences interact with same drugs. In addition, though several other similarity metrics have been developed to predict DTIs, the combination of multiple similarity metrics (especially heterogeneous similarities) is too naïve to sufficiently explore the multiple similarities. In this paper, based on Gene Ontology and pathway annotation, we introduce two novel target similarity metrics to address above issues. More importantly, we propose a more effective strategy via decision template to integrate multiple classifiers designed with multiple similarity metrics. In the scenarios that predict existing targets for new drugs and predict approved drugs for new protein targets, the results on the DTI benchmark datasets show that our target similarity metrics are able to enhance the predictive accuracies in two scenarios. And the elaborate fusion strategy of multiple classifiers has better predictive power than the naïve combination of multiple similarity metrics. Compared with other two state-of-the-art approaches on the four popular benchmark datasets of binary drug-target interactions, our method achieves the best results in terms of AUC and AUPR for predicting available targets for new drugs (S2), and predicting approved drugs for new protein targets (S3).These results demonstrate that our method can effectively predict the drug-target interactions. The software package can freely available at https://github.com/NwpuSY/DT_all.git for academic users. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
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Insights into dietary flavonoids as molecular templates for the design of anti-platelet drugs
Wright, Bernice; Spencer, Jeremy P.E.; Lovegrove, Julie A.; Gibbins, Jonathan M.
2013-01-01
Flavonoids are low-molecular weight, aromatic compounds derived from fruits, vegetables, and other plant components. The consumption of these phytochemicals has been reported to be associated with reduced cardiovascular disease (CVD) risk, attributed to their anti-inflammatory, anti-proliferative, and anti-thrombotic actions. Flavonoids exert these effects by a number of mechanisms which include attenuation of kinase activity mediated at the cell-receptor level and/or within cells, and are characterized as broad-spectrum kinase inhibitors. Therefore, flavonoid therapy for CVD is potentially complex; the use of these compounds as molecular templates for the design of selective and potent small-molecule inhibitors may be a simpler approach to treat this condition. Flavonoids as templates for drug design are, however, poorly exploited despite the development of analogues based on the flavonol, isoflavonone, and isoflavanone subgroups. Further exploitation of this family of compounds is warranted due to a structural diversity that presents great scope for creating novel kinase inhibitors. The use of computational methodologies to define the flavonoid pharmacophore together with biological investigations of their effects on kinase activity, in appropriate cellular systems, is the current approach to characterize key structural features that will inform drug design. This focussed review highlights the potential of flavonoids to guide the design of clinically safer, more selective, and potent small-molecule inhibitors of cell signalling, applicable to anti-platelet therapy. PMID:23024269
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Mullen, Douglas G; Banaszak Holl, Mark M
2011-11-15
Nanoparticles conjugated with functional ligands are expected to have a major impact in medicine, photonics, sensing, and nanoarchitecture design. One major obstacle to realizing the promise of these materials, however, is the difficulty in controlling the ligand/nanoparticle ratio. This obstacle can be segmented into three key areas: First, many designs of these systems have failed to account for the true heterogeneity of ligand/nanoparticle ratios that compose each material. Second, studies in the field often use the mean ligand/nanoparticle ratio as the accepted level of characterization of these materials. This measure is insufficient because it does not provide information about the distribution of ligand/nanoparticle species within a sample or the number and relative amount of the different species that compose a material. Without these data, researchers do not have an accurate definition of material composition necessary both to understand the material-property relationships and to monitor the consistency of the material. Third, some synthetic approaches now in use may not produce consistent materials because of their sensitivity to reaction kinetics and to the synthetic history of the nanoparticle. In this Account, we describe recent advances that we have made in under standing the material composition of ligand-nanoparticle systems. Our work has been enabled by a model system using poly(amidoamine) dendrimers and two small molecule ligands. Using reverse phase high-pressure liquid chromatography (HPLC), we have successfully resolved and quantified the relative amounts and ratios of each ligand/dendrimer combination. This type of information is rare within the field of ligand-nanoparticle materials because most analytical techniques have been unable to identify the components in the distribution. Our experimental data indicate that the actual distribution of ligand-nanoparticle components is much more heterogeneous than is commonly assumed. The mean ligand/nanoparticle ratio that is typically the only information known about a material is insufficient because the mean does not provide information on the diversity of components in the material and often does not describe the most common component (the mode). Additionally, our experimental data has provided examples of material batches with the same mean ligand/nanoparticle ratio and very different distributions. This discrepancy indicates that the mean cannot be used as the sole metric to assess the reproducibility of a system. We further found that distribution profiles can be highly sensitive to the synthetic history of the starting material as well as slight changes in reaction conditions. We have incorporated the lessons from our experimental data into the design of new ligand-nanoparticle systems to provide improved control over these ratios.
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Mendoza-Espinosa, Daniel; Donnadieu, Bruno
2011-01-01
A series of bimetallic complexes supported by a 4-phosphino substituted NHC ligand have been synthesized. The use of the stable ligand reduces the number of synthetic steps and allows for a wide range of metal combinations. PMID:21322115
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Group Additivity in Ligand Binding Affinity: An Alternative Approach to Ligand Efficiency.
Reynolds, Charles H; Reynolds, Ryan C
2017-12-26
Group additivity is a concept that has been successfully applied to a variety of thermochemical and kinetic properties. This includes drug discovery, where functional group additivity is often assumed in ligand binding. Ligand efficiency can be recast as a special case of group additivity where ΔG/HA is the group equivalent (HA is the number of non-hydrogen atoms in a ligand). Analysis of a large data set of protein-ligand binding affinities (K i ) for diverse targets shows that in general ligand binding is distinctly nonlinear. It is possible to create a group equivalent scheme for ligand binding, but only in the context of closely related proteins, at least with regard to size. This finding has broad implications for drug design from both experimental and computational points of view. It also offers a path forward for a more general scheme to assess the efficiency of ligand binding.
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Mapping of ligand-binding cavities in proteins.
Andersson, C David; Chen, Brian Y; Linusson, Anna
2010-05-01
The complex interactions between proteins and small organic molecules (ligands) are intensively studied because they play key roles in biological processes and drug activities. Here, we present a novel approach to characterize and map the ligand-binding cavities of proteins without direct geometric comparison of structures, based on Principal Component Analysis of cavity properties (related mainly to size, polarity, and charge). This approach can provide valuable information on the similarities and dissimilarities, of binding cavities due to mutations, between-species differences and flexibility upon ligand-binding. The presented results show that information on ligand-binding cavity variations can complement information on protein similarity obtained from sequence comparisons. The predictive aspect of the method is exemplified by successful predictions of serine proteases that were not included in the model construction. The presented strategy to compare ligand-binding cavities of related and unrelated proteins has many potential applications within protein and medicinal chemistry, for example in the characterization and mapping of "orphan structures", selection of protein structures for docking studies in structure-based design, and identification of proteins for selectivity screens in drug design programs. 2009 Wiley-Liss, Inc.
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Mapping of Ligand-Binding Cavities in Proteins
Andersson, C. David; Chen, Brian Y.; Linusson, Anna
2010-01-01
The complex interactions between proteins and small organic molecules (ligands) are intensively studied because they play key roles in biological processes and drug activities. Here, we present a novel approach to characterise and map the ligand-binding cavities of proteins without direct geometric comparison of structures, based on Principal Component Analysis of cavity properties (related mainly to size, polarity and charge). This approach can provide valuable information on the similarities, and dissimilarities, of binding cavities due to mutations, between-species differences and flexibility upon ligand-binding. The presented results show that information on ligand-binding cavity variations can complement information on protein similarity obtained from sequence comparisons. The predictive aspect of the method is exemplified by successful predictions of serine proteases that were not included in the model construction. The presented strategy to compare ligand-binding cavities of related and unrelated proteins has many potential applications within protein and medicinal chemistry, for example in the characterisation and mapping of “orphan structures”, selection of protein structures for docking studies in structure-based design and identification of proteins for selectivity screens in drug design programs. PMID:20034113
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Lipinski, Christopher A
2016-06-01
The rule of five (Ro5), based on physicochemical profiles of phase II drugs, is consistent with structural limitations in protein targets and the drug target ligands. Three of four parameters in Ro5 are fundamental to the structure of both target and drug binding sites. The chemical structure of the drug ligand depends on the ligand chemistry and design philosophy. Two extremes of chemical structure and design philosophy exist; ligands constructed in the medicinal chemistry synthesis laboratory without input from natural selection and natural product (NP) metabolites biosynthesized based on evolutionary selection. Exceptions to Ro5 are found mostly among NPs. Chemistry chameleon-like behavior of some NPs due to intra-molecular hydrogen bonding as exemplified by cyclosporine A is a strong contributor to NP Ro5 outliers. The fragment derived, drug Navitoclax is an example of the extensive expertise, resources, time and key decisions required for the rare discovery of a non-NP Ro5 outlier. Copyright © 2016 Elsevier B.V. All rights reserved.
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Identifying Key Factors Relevant for Base Camp Siting
2017-12-01
designated by other authorized documents. DESTROY THIS REPORT WHEN NO LONGER NEEDED. DO NOT RETURN IT TO THE ORIGINATOR. ERDC TR-17-17 iii Contents...Criteria Framework .......................................................................................... 6 3.1 Design templates...18 Tables Table 1. Design choice factors. Each
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Inter-ictal spike detection using a database of smart templates.
Lodder, Shaun S; Askamp, Jessica; van Putten, Michel J A M
2013-12-01
Visual analysis of EEG is time consuming and suffers from inter-observer variability. Assisted automated analysis helps by summarizing key aspects for the reviewer and providing consistent feedback. Our objective is to design an accurate and robust system for the detection of inter-ictal epileptiform discharges (IEDs) in scalp EEG. IED Templates are extracted from the raw data of an EEG training set. By construction, the templates are given the ability to learn by searching for other IEDs within the training set using a time-shifted correlation. True and false detections are remembered and classifiers are trained for improving future predictions. During detection, trained templates search for IEDs in the new EEG. Overlapping detections from all templates are grouped and form one IED. Certainty values are added based on the reliability of the templates involved. For evaluation, 2160 templates were used on an evaluation dataset of 15 continuous recordings containing 241 IEDs (0.79/min). Sensitivities up to 0.99 (7.24fp/min) were reached. To reduce false detections, higher certainty thresholds led to a mean sensitivity of 0.90 with 2.36fp/min. By using many templates, this technique is less vulnerable to variations in spike morphology. A certainty value for each detection allows the system to present findings in a more efficient manner and simplifies the review process. Automated spike detection can assist in visual interpretation of the EEG which may lead to faster review times. Copyright © 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
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Azimifar, Farhad; Hassani, Kamran; Saveh, Amir Hossein; Ghomsheh, Farhad Tabatabai
2017-11-14
Several methods including free-hand technique, fluoroscopic guidance, image-guided navigation, computer-assisted surgery system, robotic platform and patient's specific templates are being used for pedicle screw placement. These methods have screw misplacements and are not always easy to be applied. Furthermore, it is necessary to expose completely a large portions of the spine in order to access fit entirely around the vertebrae. In this study, a multi-level patient's specific template with medium invasiveness was proposed for pedicle screw placement in the scoliosis surgery. It helps to solve the problems related to the soft tissues removal. After a computer tomography (CT) scan of the spine, the templates were designed based on surgical considerations. Each template was manufactured using three-dimensional printing technology under a semi-flexible post processing. The templates were placed on vertebras at four points-at the base of the superior-inferior articular processes on both left-right sides. This helps to obtain less invasive and more accurate procedure as well as true-stable and easy placement in a unique position. The accuracy of screw positions was confirmed by CT scan after screw placement. The result showed the correct alignment in pedicle screw placement. In addition, the template has been initially tested on a metal wire series Moulage (height 70 cm and material is PVC). The results demonstrated that it could be possible to implement it on a real patient. The proposed template significantly reduced screw misplacements, increased stability, and decreased the sliding & the intervention invasiveness.
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Raschka, Sebastian; Wolf, Alex J; Bemister-Buffington, Joseph; Kuhn, Leslie A
2018-04-01
Understanding how proteins encode ligand specificity is fascinating and similar in importance to deciphering the genetic code. For protein-ligand recognition, the combination of an almost infinite variety of interfacial shapes and patterns of chemical groups makes the problem especially challenging. Here we analyze data across non-homologous proteins in complex with small biological ligands to address observations made in our inhibitor discovery projects: that proteins favor donating H-bonds to ligands and avoid using groups with both H-bond donor and acceptor capacity. The resulting clear and significant chemical group matching preferences elucidate the code for protein-native ligand binding, similar to the dominant patterns found in nucleic acid base-pairing. On average, 90% of the keto and carboxylate oxygens occurring in the biological ligands formed direct H-bonds to the protein. A two-fold preference was found for protein atoms to act as H-bond donors and ligand atoms to act as acceptors, and 76% of all intermolecular H-bonds involved an amine donor. Together, the tight chemical and geometric constraints associated with satisfying donor groups generate a hydrogen-bonding lock that can be matched only by ligands bearing the right acceptor-rich key. Measuring an index of H-bond preference based on the observed chemical trends proved sufficient to predict other protein-ligand complexes and can be used to guide molecular design. The resulting Hbind and Protein Recognition Index software packages are being made available for rigorously defining intermolecular H-bonds and measuring the extent to which H-bonding patterns in a given complex match the preference key.
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NASA Astrophysics Data System (ADS)
Raschka, Sebastian; Wolf, Alex J.; Bemister-Buffington, Joseph; Kuhn, Leslie A.
2018-02-01
Understanding how proteins encode ligand specificity is fascinating and similar in importance to deciphering the genetic code. For protein-ligand recognition, the combination of an almost infinite variety of interfacial shapes and patterns of chemical groups makes the problem especially challenging. Here we analyze data across non-homologous proteins in complex with small biological ligands to address observations made in our inhibitor discovery projects: that proteins favor donating H-bonds to ligands and avoid using groups with both H-bond donor and acceptor capacity. The resulting clear and significant chemical group matching preferences elucidate the code for protein-native ligand binding, similar to the dominant patterns found in nucleic acid base-pairing. On average, 90% of the keto and carboxylate oxygens occurring in the biological ligands formed direct H-bonds to the protein. A two-fold preference was found for protein atoms to act as H-bond donors and ligand atoms to act as acceptors, and 76% of all intermolecular H-bonds involved an amine donor. Together, the tight chemical and geometric constraints associated with satisfying donor groups generate a hydrogen-bonding lock that can be matched only by ligands bearing the right acceptor-rich key. Measuring an index of H-bond preference based on the observed chemical trends proved sufficient to predict other protein-ligand complexes and can be used to guide molecular design. The resulting Hbind and Protein Recognition Index software packages are being made available for rigorously defining intermolecular H-bonds and measuring the extent to which H-bonding patterns in a given complex match the preference key.
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Ozawa, Motoyasu; Ozawa, Tomonaga; Ueda, Kazuyoshi
2017-06-01
The molecular interactions of inhibitors of bromodomains (BRDs) were investigated. BRDs are protein interaction modules that recognizing ε-N-acetyl-lysine (εAc-Lys) motifs found in histone tails and are promising protein-protein interaction (PPI) targets. First, we analyzed a peptide ligand containing εAc-Lys to evaluate native PPIs. We then analyzed tetrahydroquinazoline-6-yl-benzensulfonamide derivatives found by fragment-based drug design (FBDD) and examined their interactions with the protein compared with the peptide ligand in terms of the inter-fragment interaction energy. In addition, we analyzed benzodiazepine derivatives that are high-affinity ligands for BRDs and examined differences in the CH/π interactions of the amino acid residues. We further surveyed changes in the charges of the amino acid residues among individual ligands, performed pair interaction energy decomposition analysis and estimated the water profile within the ligand binding site. Thus, useful insights for drug design were provided. Through these analyses and considerations, we show that the FMO method is a useful drug design tool to evaluate the process of FBDD and to explore PPI inhibitors. Copyright © 2017 Elsevier Inc. All rights reserved.
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Beyond small molecule SAR – using the dopamine D3 receptor crystal structure to guide drug design
Keck, Thomas M.; Burzynski, Caitlin; Shi, Lei; Newman, Amy Hauck
2016-01-01
The dopamine D3 receptor is a target of pharmacotherapeutic interest in a variety of neurological disorders including schizophrenia, restless leg syndrome, and drug addiction. The high protein sequence homology between the D3 and D2 receptors has posed a challenge to developing D3 receptor-selective ligands whose behavioral actions can be attributed to D3 receptor engagement, in vivo. However, through primarily small molecule structure-activity relationship (SAR) studies, a variety of chemical scaffolds have been discovered over the past two decades that have resulted in several D3 receptor-selective ligands with high affinity and in vivo activity. Nevertheless, viable clinical candidates remain limited. The recent determination of the high-resolution crystal structure of the D3 receptor has invigorated structure-based drug design, providing refinements to the molecular dynamic models and testable predictions about receptor-ligand interactions. This review will highlight recent preclinical and clinical studies demonstrating potential utility of D3 receptor-selective ligands in the treatment of addiction. In addition, new structure-based rational drug design strategies for D3 receptor-selective ligands that complement traditional small molecule SAR to improve the selectivity and directed efficacy profiles are examined. PMID:24484980
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Kaneyama, Shuichi; Sugawara, Taku; Sumi, Masatoshi
2015-03-15
Clinical trial for midcervical pedicle screw insertion using a novel patient-specific intraoperative screw guiding device. To evaluate the availability of the "Screw Guide Template" (SGT) system for insertion of midcervical pedicle screws. Despite many efforts for accurate midcervical pedicle screw insertion, there still remain unacceptable rate of screw malpositioning that might cause neurovascular injuries. We developed patient-specific SGT system for safe and accurate intraoperative screw navigation tool and have reported its availability for the screw insertion to C2 vertebra and thoracic spine. Preoperatively, the bone image on computed tomography was analyzed and the trajectories of the screws were designed in 3-dimensional format. Three types of templates were created for each lamina: location template, drill guide template, and screw guide template. During the operations, after engaging the templates directly with the laminae, drilling, tapping, and screwing were performed with each template. We placed 80 midcervical pedicle screws for 20 patients. The accuracy and safety of the screw insertion by SGT system were evaluated using postoperative computed tomographic scan by calculation of screw deviation from the preplanned trajectory and evaluation of screw breach of pedicle wall. All templates fitted the laminae and screw navigation procedures proceeded uneventfully. All screws were inserted accurately with the mean screw deviation from planned trajectory of 0.29 ± 0.31 mm and no neurovascular complication was experienced. We demonstrated that our SGT system could support the precise screw insertion in midcervical pedicle. SGT prescribes the safe screw trajectory in a 3-dimensional manner and the templates fit and lock directly to the target laminae, which prevents screwing error along with the change of spinal alignment during the surgery. These advantages of the SGT system guarantee the high accuracy in screw insertion, which allowed surgeons to insert cervical pedicle screws safely. 3.
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Comparison of five-axis milling and rapid prototyping for implant surgical templates.
Park, Ji-Man; Yi, Tae-Kyoung; Koak, Jai-Young; Kim, Seong-Kyoon; Park, Eun-Jin; Heo, Seong-Joo
2014-01-01
This study aims to compare and evaluate the accuracy of surgical templates fabricated using coordinate synchronization processing with five-axis milling and design-related processing with rapid prototyping (RP). Master phantoms with 10 embedded gutta-percha cylinders hidden under artificial gingiva were fabricated and imaged using cone beam computed tomography. Vectors of the hidden cylinders were extracted and transferred to those of the planned implants through reverse engineering using virtual planning software. An RP-produced template was fabricated by stereolithography in photopolymer at the RP center according to planned data. Metal sleeves were bonded after holes were bored (group RP). For the milled template, milling coordinates were synchronized using the conversion process for the coordinate synchronization platform located on the model's bottom. Metal bushings were set on holes milled on the five-axis milling machine, on which the model was fixed through the coordinate synchronization plate, and the framework was constructed on the model using orthodontic resin (group CS). A computed tomography image was taken with templates firmly fixed on models using anchor pins (RP) or anchor screws (CS). The accuracy was analyzed via reverse engineering. Differences between the two groups were compared by repeated measures two-factor analysis. From the reverse-engineered image of the template on the experimental model, RP-produced templates showed significantly larger deviations than did milled surgical guides. Maximum deviations of the group RP were 1.58 mm (horizontal), 1.68 mm (vertical), and 8.51 degrees (angular); those of the group CS were 0.68 mm (horizontal), 0.41 mm (vertical), and 3.23 degrees (angular). A comparison of milling and RP template production methods showed that a vector-milled surgical guide had significantly smaller deviations than did an RP-produced template. The accuracy of computer-guided milled surgical templates was within the safety margin of previous studies.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Galati, Elizabeth; Tebbe, Moritz; Querejeta-Fernández, Ana
Chemically and topographically patterned nanoparticles (NPs) with dimensions on the order of tens of nanometers have a diverse range of applications and are a valuable system for fundamental research. Recently, thermodynamically controlled segregation of a smooth layer of polymer ligands into pinned micelles (patches) offered an approach to nanopatterning of polymer-functionalized NPs. Control of the patch number, size, and spatial distribution on the surface of spherical NPs has been achieved, however, the role of NP shape remained elusive. Here, we report the role of NP shape, namely, the effect of the local surface curvature, on polymer segregation into surface patches.more » For polymer-functionalized metal nanocubes, we show experimentally and theoretically that the patches form preferentially on the high-curvature regions such as vertices and edges. An in situ transformation of the nanocubes into nanospheres leads to the change in the number and distribution of patches; a process that is dominated by the balance between the surface energy and the stretching energy of the polymer ligands. The experimental and theoretical results presented in this work are applicable to surface patterning of polymer-capped NPs with different shapes, which then enables the exploration of patch-directed self-assembly, as colloidal surfactants, and as templates for the synthesis of hybrid nanomaterials.« less
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NASA Astrophysics Data System (ADS)
Emam, Sanaa Moustafa
2017-04-01
Some new metal(II) complexes of asymmetric Schiff base ligand were prepared by template technique. The shaped complexes are in binuclear structures and were explained through elemental analysis, molar conductivity, various spectroscopic methods (IR, U.V-Vis, XRD, ESR), thermal (TG) and magnetic moment measurements. The IR spectra were done demonstrating that the Schiff base ligand acts as neutral tetradentate moiety in all metal complexes. The electronic absorption spectra represented octahedral geometry for all complexes, while, the ESR spectra for Cu(II) complex showed axially symmetric g-tensor parameter with g׀׀ > g⊥ > 2.0023 indicating to 2B1g ground state with (dx2-y2)1 configuration. The nature of the solid residue created from TG estimations was affirmed utilizing IR and XRD spectra. The biological activity of the prepared complexes was studied against Land Snails. Additionally, the in vitro antitumor activity of the synthesized complexes with Hepatocellular Carcinoma cell (Hep-G2) was examined. It was observed that Zn(II) complex (5), exhibits a high inhibition of growth of the cell line with IC50 of 7.09 μg/mL.
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Design, Fabrication, Characterization and Modeling of Integrated Functional Materials
2014-10-01
oxide ( AAO ) membranes were fabricated from high purity aluminum foil (99.999%) by electrochemical route using a controlled two-step anodization ...deposition of Fe and Co in anodized alumina templates. We used commercially prepared AAO templates which had pore diameters of 100 nm (300 nm), an...a thermal decomposition method. The final product was suspended in high-purity hexane to create a ferrofluid. Custom highly ordered anodic aluminum
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Self-templating synthesis of hollow spheres of MOFs and their derived nanostructures.
Chuan Tan, Ying; Chun Zeng, Hua
2016-10-04
An aqueous one-pot self-templating synthesis method to prepare highly uniform ZIF-67 hollow spheres (ZIF-67-HS) and their transition metal-doped derivatives (M/ZIF-67-HS, M = Cu and/or Zn) was developed. Extension of this approach to another important class of MOFs (metal carboxylates; e.g., HKUST-1) and facile design of derived nanostructures with complex architectures were also achieved.
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Integrated Flexible Electronic Devices Based on Passive Alignment for Physiological Measurement
Ryu, Jin Hwa; Byun, Sangwon; Baek, In-Bok; Lee, Bong Kuk; Jang, Won Ick; Jang, Eun-Hye; Kim, Ah-Yung; Yu, Han Yung
2017-01-01
This study proposes a simple method of fabricating flexible electronic devices using a metal template for passive alignment between chip components and an interconnect layer, which enabled efficient alignment with high accuracy. An electrocardiogram (ECG) sensor was fabricated using 20 µm thick polyimide (PI) film as a flexible substrate to demonstrate the feasibility of the proposed method. The interconnect layer was fabricated by a two-step photolithography process and evaporation. After applying solder paste, the metal template was placed on top of the interconnect layer. The metal template had rectangular holes at the same position as the chip components on the interconnect layer. Rectangular hole sizes were designed to account for alignment tolerance of the chips. Passive alignment was performed by simply inserting the components in the holes of the template, which resulted in accurate alignment with positional tolerance of less than 10 µm based on the structural design, suggesting that our method can efficiently perform chip mounting with precision. Furthermore, a fabricated flexible ECG sensor was easily attachable to the curved skin surface and able to measure ECG signals from a human subject. These results suggest that the proposed method can be used to fabricate epidermal sensors, which are mounted on the skin to measure various physiological signals. PMID:28420219
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Lau, Kai Lin; Sleiman, Hanadi F
2016-07-26
Given its highly predictable self-assembly properties, DNA has proven to be an excellent template toward the design of functional materials. Prominent examples include the remarkable complexity provided by DNA origami and single-stranded tile (SST) assemblies, which require hundreds of unique component strands. However, in many cases, the majority of the DNA assembly is purely structural, and only a small "working area" needs to be aperiodic. On the other hand, extended lattices formed by DNA tile motifs require only a few strands; but they suffer from lack of size control and limited periodic patterning. To overcome these limitations, we adopt a templation strategy, where an input strand of DNA dictates the size and patterning of resultant DNA tile structures. To prepare these templating input strands, a sequential growth technique developed in our lab is used, whereby extended DNA strands of defined sequence and length may be generated simply by controlling their order of addition. With these, we demonstrate the periodic patterning of size-controlled double-crossover (DX) and triple-crossover (TX) tile structures, as well as intentionally designed aperiodicity of a DX tile structure. As such, we are able to prepare size-controlled DNA structures featuring aperiodicity only where necessary with exceptional economy and efficiency.
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3D Printing of Hierarchical Silk Fibroin Structures.
Sommer, Marianne R; Schaffner, Manuel; Carnelli, Davide; Studart, André R
2016-12-21
Like many other natural materials, silk is hierarchically structured from the amino acid level up to the cocoon or spider web macroscopic structures. Despite being used industrially in a number of applications, hierarchically structured silk fibroin objects with a similar degree of architectural control as in natural structures have not been produced yet due to limitations in fabrication processes. In a combined top-down and bottom-up approach, we exploit the freedom in macroscopic design offered by 3D printing and the template-guided assembly of ink building blocks at the meso- and nanolevel to fabricate hierarchical silk porous materials with unprecedented structural control. Pores with tunable sizes in the range 40-350 μm are generated by adding sacrificial organic microparticles as templates to a silk fibroin-based ink. Commercially available wax particles or monodisperse polycaprolactone made by microfluidics can be used as microparticle templates. Since closed pores are generated after template removal, an ultrasonication treatment can optionally be used to achieve open porosity. Such pore templating particles can be further modified with nanoparticles to create a hierarchical template that results in porous structures with a defined nanotopography on the pore walls. The hierarchically porous silk structures obtained with this processing technique can potentially be utilized in various application fields from structural materials to thermal insulation to tissue engineering scaffolds.
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CLINICAL APPLICATION OF A DRILL GUIDE TEMPLATE FOR PEDICLE SCREW PLACEMENT IN SEVERE SCOLIOSIS.
Li, Xin; Zhang, Yaoshen; Zhang, Qiang; Zhao, Changsong; Liu, Kun
2017-01-01
To evaluate the accuracy and the effect of drill guide template for pedicle screw placement in severe scoliosis. Eight patients with rigid scoliosis were enrolled, five males and three females, ranging from nine to 23 years old. A three-dimensional CT scan of the spine was performed and saved as a DICOM file type. The multi-level template was designed by Mimics software and manufactured according to the part of the most severe deformity. The drill template was placed on the corresponding vertebral surface. Pedicle screws were carefully inserted across the trajectory of the template. Postoperatively, the positions of the pedicle screws were evaluated by CT scan and graded for validation. No spinal cord injury or nerve damage occurred. All patients had satisfactory outcomes. The abnormalities and the measures observed during operation were the same as those found in the preoperative period. The position of the pedicle screws was accurate, according to the postoperative X-ray and CT scan. The rate of scoliosis correction was 60%. Compared with controls, surgery time, blood loss and radiation were significantly lower. With the application of multi-level template, the placement of pedicle screws shows high accuracy in scoliosis with shorter surgical time, less blood loss and less radiation exposure. Level of Evidence III, Retrospective Comparative Study.
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Remote site-selective C–H activation directed by a catalytic bifunctional template
Zhang, Zhipeng; Tanaka, Keita; Yu, Jin-Quan
2017-01-01
Converting C–H bonds directly into carbon-carbon and carbon-heteroatom bonds can significantly improve step-economy in synthesis by providing alternative disconnections to traditional functional group manipulations. In this context, directed C–H activation reactions have been extensively explored for regioselective functionalization1-5. Though applicability can be severely curtailed by distance from the directing group and the shape of the molecule, a number of approaches have been developed to overcome this limitation6-12. For instance, recognition of the distal and geometric relationship between an existing functional group and multiple C–H bonds has recently been exploited to achieve meta-selective C–H activation by use of a covalently attached U-shaped template13-17. However, stoichiometric installation of the template is not feasible in the absence of an appropriate functional group handle. Here we report the design of a catalytic, bifunctional template that binds heterocyclic substrate via reversible coordination instead of covalent linkage, allowing remote site-selective C–H olefination of heterocycles. The two metal centers coordinated to this template play different roles; anchoring substrates to the proximity of catalyst and cleaving the remote C–H bonds respectively. Using this strategy, we demonstrate remote site-selective C–H olefination of heterocyclic substrates which do not have functional group handles for covalently attaching templates. PMID:28273068
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Are care plans suitable for the management of multiple conditions?
Young, Charlotte E.; Boyle, Frances M.; Mutch, Allyson J.
2016-01-01
Background Care plans have been part of the primary care landscape in Australia for almost two decades. With an increasing number of patients presenting with multiple chronic conditions, it is timely to consider whether care plans meet the needs of patients and clinicians. Objectives To review and benchmark existing care plan templates that include recommendations for comorbid conditions, against four key criteria: (i) patient preferences, (ii) setting priorities, (iii) identifying conflicts and synergies between conditions, and (iv) setting dates for reviewing the care plan. Design Document analysis of Australian care plan templates published from 2006 to 2014 that incorporated recommendations for managing comorbid conditions in primary care. Results Sixteen templates were reviewed. All of the care plan templates addressed patient preference, but this was not done comprehensively. Only three templates included setting priorities. None assisted in identifying conflicts and synergies between conditions. Fifteen templates included setting a date for reviewing the care plan. Conclusions Care plans are a well-used tool in primary care practice, but their current format perpetuates a single-disease approach to care, which works contrary to their intended purpose. Restructuring care plans to incorporate shared decision-making and attention to patient preferences may assist in shifting the focus back to the patient and their care needs. PMID:29090181
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Mosley, Ralph T.; Edwards, Thomas E.; Murakami, Eisuke
The replication of the hepatitis C viral (HCV) genome is accomplished by the NS5B RNA-dependent RNA polymerase (RdRp), for which mechanistic understanding and structure-guided drug design efforts have been hampered by its propensity to crystallize in a closed, polymerization-incompetent state. The removal of an autoinhibitory {beta}-hairpin loop from genotype 2a HCV NS5B increases de novo RNA synthesis by >100-fold, promotes RNA binding, and facilitated the determination of the first crystallographic structures of HCV polymerase in complex with RNA primer-template pairs. These crystal structures demonstrate the structural realignment required for primer-template recognition and elongation, provide new insights into HCV RNA synthesismore » at the molecular level, and may prove useful in the structure-based design of novel antiviral compounds. Additionally, our approach for obtaining the RNA primer-template-bound structure of HCV polymerase may be generally applicable to solving RNA-bound complexes for other viral RdRps that contain similar regulatory {beta}-hairpin loops, including bovine viral diarrhea virus, dengue virus, and West Nile virus.« less
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Sheng, Qinglin; Zheng, Jianbin
2009-02-15
A novel method based on covalent attachment of two enzymes, glucose oxidase (GOD) and horseradish peroxide (HRP), onto carboxylic-derived multiwalled carbon nanotubes (MWNTs) for the deposition of electroactive polyaniline (PANI) under ambient conditions is described. Ultraviolet-visible spectroscopy, Fourier-transform infrared (FTIR) spectroscopy, and transmission electron microscopy were used to characterize the assembling of bienzyme and the morphology of PANI|MWNTs. Under the bienzyme biocatalytic condition, a head-to-tail structure of PANI templated by MWNTs was formed. The voltammetric characteristics of the resulting biosensor were investigated by cyclic voltammetry in the presence of glucose. The current response of PANI was linearly related to glucose concentration between 0.05 and 12.0mM with a correlation coefficient of 0.994. The synergistic performance of bienzyme, highly efficient polymerization, and templated deposition provide a general platform for the synthesis of nanowires and nanocircuits, the construction of bioelectronic devices, and the design of novel biosensors.
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Bernardes, Amanda; Souza, Paulo C T; Muniz, João R C; Ricci, Clarisse G; Ayers, Stephen D; Parekh, Nili M; Godoy, André S; Trivella, Daniela B B; Reinach, Peter; Webb, Paul; Skaf, Munir S; Polikarpov, Igor
2013-08-23
Peroxisome proliferator-activated receptors (PPARs) are members of a superfamily of nuclear transcription factors. They are involved in mediating numerous physiological effects in humans, including glucose and lipid metabolism. PPARα ligands effectively treat dyslipidemia and have significant antiinflammatory and anti-atherosclerotic activities. These effects and their ligand-dependent activity make nuclear receptors obvious targets for drug design. Here, we present the structure of the human PPARα in complex with WY14643, a member of fibrate class of drug, and a widely used PPAR activator. The crystal structure of this complex suggests that WY14643 induces activation of PPARα in an unusual bipartite mechanism involving conventional direct helix 12 stabilization and an alternative mode that involves a second ligand in the pocket. We present structural observations, molecular dynamics and activity assays that support the importance of the second site in WY14643 action. The unique binding mode of WY14643 reveals a new pattern of nuclear receptor ligand recognition and suggests a novel basis for ligand design, offering clues for improving the binding affinity and selectivity of ligand. We show that binding of WY14643 to PPARα was associated with antiinflammatory disease in a human corneal cell model, suggesting possible applications for PPARα ligands. Copyright © 2013 Elsevier Ltd. All rights reserved.
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Laguerre, Aurélien; Stefan, Loic; Larrouy, Manuel; Genest, David; Novotna, Jana; Pirrotta, Marc; Monchaud, David
2014-09-03
Recent and unambiguous evidences of the formation of DNA and RNA G-quadruplexes in cells has provided solid support for these structures to be considered as valuable targets in oncology. Beyond this, they have lent further credence to the anticancer strategies relying on small molecules that selectively target these higher-order DNA/RNA architectures, referred to as G-quadruplex ligands. They have also shed bright light on the necessity of designing multitasking ligands, displaying not only enticing quadruplex interacting properties (affinity, structural selectivity) but also additional features that make them usable for detecting quadruplexes in living cells, notably for determining whether, when, and where these structures fold and unfold during the cell cycle and also for better assessing the consequences of their stabilization by external agents. Herein, we report a brand new design of such multitasking ligands, whose structure experiences a quadruplex-promoted conformational switch that triggers not only its quadruplex affinity (i.e., smart ligands, which display high affinity and selectivity for DNA/RNA quadruplexes) but also its fluorescence (i.e., smart probes, which behave as selective light-up fluorescent reporters on the basis of a fluorogenic electron redistribution). The first prototype of such multifunctional ligands, termed PyroTASQ, represents a brand new generation of quadruplex ligands that can be referred to as "twice-as-smart" quadruplex ligands.
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Bryce, Richard A
2011-04-01
The ability to accurately predict the interaction of a ligand with its receptor is a key limitation in computer-aided drug design approaches such as virtual screening and de novo design. In this article, we examine current strategies for a physics-based approach to scoring of protein-ligand affinity, as well as outlining recent developments in force fields and quantum chemical techniques. We also consider advances in the development and application of simulation-based free energy methods to study protein-ligand interactions. Fuelled by recent advances in computational algorithms and hardware, there is the opportunity for increased integration of physics-based scoring approaches at earlier stages in computationally guided drug discovery. Specifically, we envisage increased use of implicit solvent models and simulation-based scoring methods as tools for computing the affinities of large virtual ligand libraries. Approaches based on end point simulations and reference potentials allow the application of more advanced potential energy functions to prediction of protein-ligand binding affinities. Comprehensive evaluation of polarizable force fields and quantum mechanical (QM)/molecular mechanical and QM methods in scoring of protein-ligand interactions is required, particularly in their ability to address challenging targets such as metalloproteins and other proteins that make highly polar interactions. Finally, we anticipate increasingly quantitative free energy perturbation and thermodynamic integration methods that are practical for optimization of hits obtained from screened ligand libraries.
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NASA Astrophysics Data System (ADS)
Gao, Fan; Huang, Liangliang; Ma, Yike; Jiao, Shufei; Jiang, Yansong; Bi, Yanfeng
2017-10-01
A new layered gallium phosphate Ga3(PO4)4(C2N2H8)·(H2C2N2H8)2·Cl (compound 1), has been ionothermally synthesized in the presence of deep eutectic solvent (DES) comprising mixtures of choline chloride and 2-imidazolidone (IMI). Single-crystal X-ray diffraction analysis reveals that compound 1 shows 2D layered framework with 10-ring windows, which is constructed from unusual heptamer second building units (SBUs). The ethylenediamine (en) units deriving from the decomposition of IMI, play a dual role as bidentate ligands coordinated with 6-fold coordinate gallium atoms and the templates. Additionally, compound 1 shows photoluminescence property in solid state at room temperature.
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Fernández-Bachiller, María Isabel; Brzozowska, Iwona; Odolczyk, Norbert; Zielenkiewicz, Urszula; Zielenkiewicz, Piotr; Rademann, Jörg
2016-01-01
Toxin–antitoxin systems constitute a native survival strategy of pathogenic bacteria and thus are potential targets of antibiotic drugs. Here, we target the Zeta–Epsilon toxin–antitoxin system, which is responsible for the stable maintenance of certain multiresistance plasmids in Gram-positive bacteria. Peptide ligands were designed on the basis of the ε2ζ2 complex. Three α helices of Zeta forming the protein–protein interaction (PPI) site were selected and peptides were designed conserving the residues interacting with Epsilon antitoxin while substituting residues binding intramolecularly to other parts of Zeta. Designed peptides were synthesized with an N-terminal fluoresceinyl-carboxy-residue for binding assays and provided active ligands, which were used to define the hot spots of the ε2ζ2 complex. Further shortening and modification of the binding peptides provided ligands with affinities <100 nM, allowing us to determine the most relevant PPIs and implement a robust competition binding assay. PMID:27438853
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Fernández-Bachiller, María Isabel; Brzozowska, Iwona; Odolczyk, Norbert; Zielenkiewicz, Urszula; Zielenkiewicz, Piotr; Rademann, Jörg
2016-07-16
Toxin-antitoxin systems constitute a native survival strategy of pathogenic bacteria and thus are potential targets of antibiotic drugs. Here, we target the Zeta-Epsilon toxin-antitoxin system, which is responsible for the stable maintenance of certain multiresistance plasmids in Gram-positive bacteria. Peptide ligands were designed on the basis of the ε₂ζ₂ complex. Three α helices of Zeta forming the protein-protein interaction (PPI) site were selected and peptides were designed conserving the residues interacting with Epsilon antitoxin while substituting residues binding intramolecularly to other parts of Zeta. Designed peptides were synthesized with an N-terminal fluoresceinyl-carboxy-residue for binding assays and provided active ligands, which were used to define the hot spots of the ε₂ζ₂ complex. Further shortening and modification of the binding peptides provided ligands with affinities <100 nM, allowing us to determine the most relevant PPIs and implement a robust competition binding assay.
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NASA Astrophysics Data System (ADS)
Zhan, Naiqian; Palui, Goutam; Safi, Malak; Mattoussi, Hedi
2014-03-01
We describe the design and synthesis of two metal-coordinating zwitterion ligands to promote the transfer of hydrophobic QDs to buffer media over broad range of conditions. The ligands are prepared by appending either one or two lipoic acid anchoring groups onto a zwitterion, LA-TEG200-ZW and bis(LA)- ZW. Combining these ligands with a photochemical reduction of the lipoic acid group in the presence of UV irradiation, provides an easy to implement method to transfer luminescent QDs to buffer media, while preserving their optical and spectroscopic properties intact. The resulting zwitterion-QDs have very thin capping shell, which allows their self-assembly with full size proteins via metal-to-histidine coordination. These conjugates have great potential for use in various bio-motivated applications.
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Funabashi, Hiroto; Takeuchi, Satoshi; Tsujimura, Seiya
2017-03-23
We designed a three-dimensional (3D) hierarchical pore structure to improve the current production efficiency and stability of direct electron transfer-type biocathodes. The 3D hierarchical electrode structure was fabricated using a MgO-templated porous carbon framework produced from two MgO templates with sizes of 40 and 150 nm. The results revealed that the optimal pore composition for a bilirubin oxidase-catalysed oxygen reduction cathode was a mixture of 33% macropores and 67% mesopores (MgOC 33 ). The macropores improve mass transfer inside the carbon material, and the mesopores improve the electron transfer efficiency of the enzyme by surrounding the enzyme with carbon.
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NASA Astrophysics Data System (ADS)
Funabashi, Hiroto; Takeuchi, Satoshi; Tsujimura, Seiya
2017-03-01
We designed a three-dimensional (3D) hierarchical pore structure to improve the current production efficiency and stability of direct electron transfer-type biocathodes. The 3D hierarchical electrode structure was fabricated using a MgO-templated porous carbon framework produced from two MgO templates with sizes of 40 and 150 nm. The results revealed that the optimal pore composition for a bilirubin oxidase-catalysed oxygen reduction cathode was a mixture of 33% macropores and 67% mesopores (MgOC33). The macropores improve mass transfer inside the carbon material, and the mesopores improve the electron transfer efficiency of the enzyme by surrounding the enzyme with carbon.
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Design of Cancelable Palmprint Templates Based on Look Up Table
NASA Astrophysics Data System (ADS)
Qiu, Jian; Li, Hengjian; Dong, Jiwen
2018-03-01
A novel cancelable palmprint templates generation scheme is proposed in this paper. Firstly, the Gabor filter and chaotic matrix are used to extract palmprint features. It is then arranged into a row vector and divided into equal size blocks. These blocks are converted to corresponding decimals and mapped to look up tables, forming final cancelable palmprint features based on the selected check bits. Finally, collaborative representation based classification with regularized least square is used for classification. Experimental results on the Hong Kong PolyU Palmprint Database verify that the proposed cancelable templates can achieve very high performance and security levels. Meanwhile, it can also satisfy the needs of real-time applications.
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Current Trends in Sensors Based on Conducting Polymer Nanomaterials
Yoon, Hyeonseok
2013-01-01
Conducting polymers represent an important class of functional organic materials for next-generation electronic and optical devices. Advances in nanotechnology allow for the fabrication of various conducting polymer nanomaterials through synthesis methods such as solid-phase template synthesis, molecular template synthesis, and template-free synthesis. Nanostructured conducting polymers featuring high surface area, small dimensions, and unique physical properties have been widely used to build various sensor devices. Many remarkable examples have been reported over the past decade. The enhanced sensitivity of conducting polymer nanomaterials toward various chemical/biological species and external stimuli has made them ideal candidates for incorporation into the design of sensors. However, the selectivity and stability still leave room for improvement. PMID:28348348
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Fuse, Shinichiro; Ohuchi, Toshiaki; Asawa, Yasunobu; Sato, Shinichi; Nakamura, Hiroyuki
2016-12-15
1,3-Disubstituted-imidazopyridines were designed for developing inhibitors against HIF-1 transcriptional activity. Designed compounds were rapidly synthesized from a key aromatic scaffold via microwave-assisted Suzuki-Miyaura coupling/CH direct arylation sequence. Evaluation of ability to inhibit the hypoxia induced transcriptional activity of HIF-1 revealed that the compound 2i and 3a retained the same level of the inhibitory activity comparing with that of known inhibitor, YC-1 (1). Identified, readily accessible 1-aryl-3-furanyl/thienyl-imidazopyridine templates should be useful for future drug development. Copyright © 2016 Elsevier Ltd. All rights reserved.