Molecular description of α-keto-based inhibitors of cruzain with activity against Chagas disease combining 3D-QSAR studies and molecular dynamics.

PubMed

Saraiva, Ádria P B; Miranda, Ricardo M; Valente, Renan P P; Araújo, Jéssica O; Souza, Rutelene N B; Costa, Clauber H S; Oliveira, Amanda R S; Almeida, Michell O; Figueiredo, Antonio F; Ferreira, João E V; Alves, Cláudio Nahum; Honorio, Kathia M

2018-04-22

In this work, a group of α-keto-based inhibitors of the cruzain enzyme with anti-chagas activity was selected for a three-dimensional quantitative structure-activity relationship study (3D-QSAR) combined with molecular dynamics (MD). Firstly, statistical models based on Partial Least Square (PLS) regression were developed employing comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) descriptors. Validation parameters (q 2 and r 2 )for the models were, respectively, 0.910 and 0.997 (CoMFA) and 0.913 and 0.992 (CoMSIA). In addition, external validation for the models using a test group revealed r 2 pred  = 0.728 (CoMFA) and 0.971 (CoMSIA). The most relevant aspect in this study was the generation of molecular fields in both favorable and unfavorable regions based on the models developed. These fields are important to interpret modifications necessary to enhance the biological activities of the inhibitors. This analysis was restricted considering the inhibitors in a fixed conformation, not interacting with their target, the cruzain enzyme. Then, MD was employed taking into account important variables such as time and temperature. MD helped describe the behavior of the inhibitors and their properties showed similar results as those generated by QSAR-3D study. © 2018 John Wiley & Sons A/S.

Meet the Molecules in Chocolate: Informal Opportunities for Building Thematic Molecular Models with Children

ERIC Educational Resources Information Center

Amey, Jennifer R.; Fletcher, Matthew D.; Fletcher, Rachael V.; Jones, Alison; Roberts, Erica W.; Roberts, Ieuan O.

2008-01-01

We describe the development and use of a molecular model building activity with a chocolate theme, suitable for a public presentation of chemistry through interaction with visitors to science festivals and museums, and as a special classroom activity during science weeks, and so forth. (Contains 3 figures.)

Combining molecular docking and QSAR studies for modeling the anti-tyrosinase activity of aromatic heterocycle thiosemicarbazone analogues

NASA Astrophysics Data System (ADS)

Dong, Huanhuan; Liu, Jing; Liu, Xiaoru; Yu, Yanying; Cao, Shuwen

2018-01-01

A collection of thirty-six aromatic heterocycle thiosemicarbazone analogues presented a broad span of anti-tyrosinase activities were designed and obtained. A robust and reliable two-dimensional quantitative structure-activity relationship model, as evidenced by the high q2 and r2 values (0.848 and 0.893, respectively), was gained based on the analogues to predict the quantitative chemical-biological relationship and the new modifier direction. Inhibitory activities of the compounds were found to greatly depend on molecular shape and orbital energy. Substituents brought out large ovality and high highest-occupied molecular orbital energy values helped to improve the activity of these analogues. The molecular docking results provided visual evidence for QSAR analysis and inhibition mechanism. Based on these, two novel tyrosinase inhibitors O04 and O05 with predicted IC50 of 0.5384 and 0.8752 nM were designed and suggested for further research.

The activation strain model and molecular orbital theory

PubMed Central

Wolters, Lando P; Bickelhaupt, F Matthias

2015-01-01

The activation strain model is a powerful tool for understanding reactivity, or inertness, of molecular species. This is done by relating the relative energy of a molecular complex along the reaction energy profile to the structural rigidity of the reactants and the strength of their mutual interactions: ΔE(ζ) = ΔEstrain(ζ) + ΔEint(ζ). We provide a detailed discussion of the model, and elaborate on its strong connection with molecular orbital theory. Using these approaches, a causal relationship is revealed between the properties of the reactants and their reactivity, e.g., reaction barriers and plausible reaction mechanisms. This methodology may reveal intriguing parallels between completely different types of chemical transformations. Thus, the activation strain model constitutes a unifying framework that furthers the development of cross-disciplinary concepts throughout various fields of chemistry. We illustrate the activation strain model in action with selected examples from literature. These examples demonstrate how the methodology is applied to different research questions, how results are interpreted, and how insights into one chemical phenomenon can lead to an improved understanding of another, seemingly completely different chemical process. WIREs Comput Mol Sci 2015, 5:324–343. doi: 10.1002/wcms.1221 PMID:26753009

Targeting CYP51 for drug design by the contributions of molecular modeling.

PubMed

Rabelo, Vitor W; Santos, Taísa F; Terra, Luciana; Santana, Marcos V; Castro, Helena C; Rodrigues, Carlos R; Abreu, Paula A

2017-02-01

CYP51 is an enzyme of sterol biosynthesis pathway present in animals, plants, protozoa and fungi. This enzyme is described as an important drug target that is still of interest. Therefore, in this work, we reviewed the structure and function of CYP51 and explored the molecular modeling approaches for the development of new antifungal and antiprotozoans that target this enzyme. Crystallographic structures of CYP51 of some organisms have already been described in the literature, which enable the construction of homology models of other organisms' enzymes and molecular docking studies of new ligands. The binding mode and interactions of some new series of azoles with antifungal or antiprotozoan activities has been studied and showed important residues of the active site. Molecular modeling is an important tool to be explored for the discovery and optimization of CYP51 inhibitors with better activities, pharmacokinetics, and toxicological profiles. © 2016 Société Française de Pharmacologie et de Thérapeutique.

Novel thrombopoietin mimetic peptides bind c-Mpl receptor: Synthesis, biological evaluation and molecular modeling.

PubMed

Liu, Yaquan; Tian, Fang; Zhi, Dejuan; Wang, Haiqing; Zhao, Chunyan; Li, Hongyu

2017-02-01

Thrombopoietin (TPO) acts in promoting the proliferation of hematopoietic stem cells and by initiating specific maturation events in megakaryocytes. Now, TPO-mimetic peptides with amino acid sequences unrelated to TPO are of considerable pharmaceutical interest. In the present paper, four new TPO mimetic peptides that bind and activate c-Mpl receptor have been identified, synthesized and tested by Dual-Luciferase reporter gene assay for biological activities. The molecular modeling research was also approached to understand key molecular mechanisms and structural features responsible for peptide binding with c-Mpl receptor. The results presented that three of four mimetic peptides showed significant activities. In addition, the molecular modeling approaches proved hydrophobic interactions were the driven positive forces for binding behavior between peptides and c-Mpl receptor. TPO peptide residues in P7, P13 and P7' positions were identified by the analysis of hydrogen bonds and energy decompositions as the key ones for benefiting better biological activities. Our data suggested the synthesized peptides have considerable potential for the future development of stable and highly active TPO mimetic peptides. Copyright © 2016 Elsevier Ltd. All rights reserved.

3D-QSAR and molecular docking studies on HIV protease inhibitors

NASA Astrophysics Data System (ADS)

Tong, Jianbo; Wu, Yingji; Bai, Min; Zhan, Pei

2017-02-01

In order to well understand the chemical-biological interactions governing their activities toward HIV protease activity, QSAR models of 34 cyclic-urea derivatives with inhibitory HIV were developed. The quantitative structure activity relationship (QSAR) model was built by using comparative molecular similarity indices analysis (CoMSIA) technique. And the best CoMSIA model has rcv2, rncv2 values of 0.586 and 0.931 for cross-validated and non-cross-validated. The predictive ability of CoMSIA model was further validated by a test set of 7 compounds, giving rpred2 value of 0.973. Docking studies were used to find the actual conformations of chemicals in active site of HIV protease, as well as the binding mode pattern to the binding site in protease enzyme. The information provided by 3D-QSAR model and molecular docking may lead to a better understanding of the structural requirements of 34 cyclic-urea derivatives and help to design potential anti-HIV protease molecules.

Modeling molecular mechanisms in the axon

NASA Astrophysics Data System (ADS)

de Rooij, R.; Miller, K. E.; Kuhl, E.

2017-03-01

Axons are living systems that display highly dynamic changes in stiffness, viscosity, and internal stress. However, the mechanistic origin of these phenomenological properties remains elusive. Here we establish a computational mechanics model that interprets cellular-level characteristics as emergent properties from molecular-level events. We create an axon model of discrete microtubules, which are connected to neighboring microtubules via discrete crosslinking mechanisms that obey a set of simple rules. We explore two types of mechanisms: passive and active crosslinking. Our passive and active simulations suggest that the stiffness and viscosity of the axon increase linearly with the crosslink density, and that both are highly sensitive to the crosslink detachment and reattachment times. Our model explains how active crosslinking with dynein motors generates internal stresses and actively drives axon elongation. We anticipate that our model will allow us to probe a wide variety of molecular phenomena—both in isolation and in interaction—to explore emergent cellular-level features under physiological and pathological conditions.

Combined 3D-QSAR, molecular docking and molecular dynamics study on thyroid hormone activity of hydroxylated polybrominated diphenyl ethers to thyroid receptors β

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Xiaolin; Ye, Li; Wang, Xiaoxiang

2012-12-15

Several recent reports suggested that hydroxylated polybrominated diphenyl ethers (HO-PBDEs) may disturb thyroid hormone homeostasis. To illuminate the structural features for thyroid hormone activity of HO-PBDEs and the binding mode between HO-PBDEs and thyroid hormone receptor (TR), the hormone activity of a series of HO-PBDEs to thyroid receptors β was studied based on the combination of 3D-QSAR, molecular docking, and molecular dynamics (MD) methods. The ligand- and receptor-based 3D-QSAR models were obtained using Comparative Molecular Similarity Index Analysis (CoMSIA) method. The optimum CoMSIA model with region focusing yielded satisfactory statistical results: leave-one-out cross-validation correlation coefficient (q{sup 2}) was 0.571 andmore » non-cross-validation correlation coefficient (r{sup 2}) was 0.951. Furthermore, the results of internal validation such as bootstrapping, leave-many-out cross-validation, and progressive scrambling as well as external validation indicated the rationality and good predictive ability of the best model. In addition, molecular docking elucidated the conformations of compounds and key amino acid residues at the docking pocket, MD simulation further determined the binding process and validated the rationality of docking results. -- Highlights: ► The thyroid hormone activities of HO-PBDEs were studied by 3D-QSAR. ► The binding modes between HO-PBDEs and TRβ were explored. ► 3D-QSAR, molecular docking, and molecular dynamics (MD) methods were performed.« less

(D)- and (L)-cyclohexenyl-G, a new class of antiviral agents: synthesis, conformational analysis, molecular modeling, and biological activity.

PubMed

Wang, J; Froeyen, M; Hendrix, C; Andrei, C; Snoeck, R; Lescrinier, E; De Clercq, E; Herdewijn, P

2001-01-01

(D)- and (L)-cyclohexeneyl-G were synthesized enantioselectively starting from (R)-carvone. Both show potent and selective anti-herpesvirus activity (HSV-1, HSV-2, VZV, CMV). Molecular modeling demonstrates that both isomers are bound in the active site of HSV-1 thymidine kinase in a high-energy conformation with the base moiety orienting in an equatorial position. It is believed that the flexibility of the cyclohexene ring is essential for their antiviral activity.

Targeted Cancer Therapy: Vital Oncogenes and a New Molecular Genetic Paradigm for Cancer Initiation Progression and Treatment.

PubMed

Willis, Rudolph E

2016-09-14

It has been declared repeatedly that cancer is a result of molecular genetic abnormalities. However, there has been no working model describing the specific functional consequences of the deranged genomic processes that result in the initiation and propagation of the cancer process during carcinogenesis. We no longer need to question whether or not cancer arises as a result of a molecular genetic defect within the cancer cell. The legitimate questions are: how and why? This article reviews the preeminent data on cancer molecular genetics and subsequently proposes that the sentinel event in cancer initiation is the aberrant production of fused transcription activators with new molecular properties within normal tissue stem cells. This results in the production of vital oncogenes with dysfunctional gene activation transcription properties, which leads to dysfunctional gene regulation, the aberrant activation of transduction pathways, chromosomal breakage, activation of driver oncogenes, reactivation of stem cell transduction pathways and the activation of genes that result in the hallmarks of cancer. Furthermore, a novel holistic molecular genetic model of cancer initiation and progression is presented along with a new paradigm for the approach to personalized targeted cancer therapy, clinical monitoring and cancer diagnosis.

Insight into the interaction mechanism of human SGLT2 with its inhibitors: 3D-QSAR studies, homology modeling, and molecular docking and molecular dynamics simulations.

PubMed

Dong, Lili; Feng, Ruirui; Bi, Jiawei; Shen, Shengqiang; Lu, Huizhe; Zhang, Jianjun

2018-03-06

Human sodium-dependent glucose co-transporter 2 (hSGLT2) is a crucial therapeutic target in the treatment of type 2 diabetes. In this study, both comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were applied to generate three-dimensional quantitative structure-activity relationship (3D-QSAR) models. In the most accurate CoMFA-based and CoMSIA-based QSAR models, the cross-validated coefficients (r 2 cv ) were 0.646 and 0.577, respectively, while the non-cross-validated coefficients (r 2 ) were 0.997 and 0.991, respectively, indicating that both models were reliable. In addition, we constructed a homology model of hSGLT2 in the absence of a crystal structure. Molecular docking was performed to explore the bonding mode of inhibitors to the active site of hSGLT2. Molecular dynamics (MD) simulations and binding free energy calculations using MM-PBSA and MM-GBSA were carried out to further elucidate the interaction mechanism. With regards to binding affinity, we found that hydrogen-bond interactions of Asn51 and Glu75, located in the active site of hSGLT2, with compound 40 were critical. Hydrophobic and electrostatic interactions were shown to enhance activity, in agreement with the results obtained from docking and 3D-QSAR analysis. Our study results shed light on the interaction mode between inhibitors and hSGLT2 and may aid in the development of C-aryl glucoside SGLT2 inhibitors.

Molecular Modeling Studies of 4,5-Dihydro-1H-pyrazolo[4,3-h] quinazoline Derivatives as Potent CDK2/Cyclin A Inhibitors Using 3D-QSAR and Docking

PubMed Central

Ai, Yong; Wang, Shao-Teng; Sun, Ping-Hua; Song, Fa-Jun

2010-01-01

CDK2/cyclin A has appeared as an attractive drug targets over the years with diverse therapeutic potentials. A computational strategy based on comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) followed by molecular docking studies were performed on a series of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as potent CDK2/cyclin A inhibitors. The CoMFA and CoMSIA models, using 38 molecules in the training set, gave r2cv values of 0.747 and 0.518 and r2 values of 0.970 and 0.934, respectively. 3D contour maps generated by the CoMFA and CoMSIA models were used to identify the key structural requirements responsible for the biological activity. Molecular docking was applied to explore the binding mode between the ligands and the receptor. The information obtained from molecular modeling studies may be helpful to design novel inhibitors of CDK2/cyclin A with desired activity. PMID:21152296

Molecular modeling studies of 4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline derivatives as potent CDK2/Cyclin a inhibitors using 3D-QSAR and docking.

PubMed

Ai, Yong; Wang, Shao-Teng; Sun, Ping-Hua; Song, Fa-Jun

2010-09-28

CDK2/cyclin A has appeared as an attractive drug targets over the years with diverse therapeutic potentials. A computational strategy based on comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) followed by molecular docking studies were performed on a series of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as potent CDK2/cyclin A inhibitors. The CoMFA and CoMSIA models, using 38 molecules in the training set, gave r(2) (cv) values of 0.747 and 0.518 and r(2) values of 0.970 and 0.934, respectively. 3D contour maps generated by the CoMFA and CoMSIA models were used to identify the key structural requirements responsible for the biological activity. Molecular docking was applied to explore the binding mode between the ligands and the receptor. The information obtained from molecular modeling studies may be helpful to design novel inhibitors of CDK2/cyclin A with desired activity.

Comparative molecular field analysis to derive pharmacophore maps for induction doses of intravenous anaesthetic agents.

PubMed

Sear, J W

2011-03-01

The present study examines the molecular basis of induction of anaesthesia by i.v. hypnotic agents using comparative molecular field analysis (CoMFA). ED(50) induction doses for 14 i.v. anaesthetics in human subjects (expressed as molar dose per kilogram body weight) were obtained from the literature. Immobilizing potency data for the same 14 agents (expressed as the EC(50) plasma free drug concentrations that abolish movement in response to a noxious stimulus in 50% patients) were taken from our previous publication. These data were used to form CoMFA models for the two aspects of anaesthetic activity. Molecular alignment was achieved by field-fit minimization techniques. The lead structure for both models was eltanolone. The final CoMFA model for the ED(50) induction dose was based on two latent variables, and explained 99.3% of the variance in observed activities. It showed good intrinsic predictability (cross-validated q(2)=0.849). The equivalent model for immobilizing activity was also based on two latent variables, with r(2)=0.988 and q(2)=0.852. Although there was a correlation between -log ED(50) and -log EC(50) (r(2)=0.779), comparison of the pharmacophore maps showed poor correlation for both electrostatic and steric regions when isocontours were constructed by linking lattice grid points, making the greatest 40% contributions; the relative contributions of electrostatic and steric interactions differing between the models (induction dose: 2.5:1; immobilizing activity 1.8:1). Comparison of two CoMFA activity models shows only small elements of commonality, suggesting that different molecular features may be responsible for these two properties of i.v. anaesthetics.

Activity coefficients from molecular simulations using the OPAS method

NASA Astrophysics Data System (ADS)

Kohns, Maximilian; Horsch, Martin; Hasse, Hans

2017-10-01

A method for determining activity coefficients by molecular dynamics simulations is presented. It is an extension of the OPAS (osmotic pressure for the activity of the solvent) method in previous work for studying the solvent activity in electrolyte solutions. That method is extended here to study activities of all components in mixtures of molecular species. As an example, activity coefficients in liquid mixtures of water and methanol are calculated for 298.15 K and 323.15 K at 1 bar using molecular models from the literature. These dense and strongly interacting mixtures pose a significant challenge to existing methods for determining activity coefficients by molecular simulation. It is shown that the new method yields accurate results for the activity coefficients which are in agreement with results obtained with a thermodynamic integration technique. As the partial molar volumes are needed in the proposed method, the molar excess volume of the system water + methanol is also investigated.

Molecular sled sequences are common in mammalian proteins.

PubMed

Xiong, Kan; Blainey, Paul C

2016-03-18

Recent work revealed a new class of molecular machines called molecular sleds, which are small basic molecules that bind and slide along DNA with the ability to carry cargo along DNA. Here, we performed biochemical and single-molecule flow stretching assays to investigate the basis of sliding activity in molecular sleds. In particular, we identified the functional core of pVIc, the first molecular sled characterized; peptide functional groups that control sliding activity; and propose a model for the sliding activity of molecular sleds. We also observed widespread DNA binding and sliding activity among basic polypeptide sequences that implicate mammalian nuclear localization sequences and many cell penetrating peptides as molecular sleds. These basic protein motifs exhibit weak but physiologically relevant sequence-nonspecific DNA affinity. Our findings indicate that many mammalian proteins contain molecular sled sequences and suggest the possibility that substantial undiscovered sliding activity exists among nuclear mammalian proteins. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Cellular automata with object-oriented features for parallel molecular network modeling.

PubMed

Zhu, Hao; Wu, Yinghui; Huang, Sui; Sun, Yan; Dhar, Pawan

2005-06-01

Cellular automata are an important modeling paradigm for studying the dynamics of large, parallel systems composed of multiple, interacting components. However, to model biological systems, cellular automata need to be extended beyond the large-scale parallelism and intensive communication in order to capture two fundamental properties characteristic of complex biological systems: hierarchy and heterogeneity. This paper proposes extensions to a cellular automata language, Cellang, to meet this purpose. The extended language, with object-oriented features, can be used to describe the structure and activity of parallel molecular networks within cells. Capabilities of this new programming language include object structure to define molecular programs within a cell, floating-point data type and mathematical functions to perform quantitative computation, message passing capability to describe molecular interactions, as well as new operators, statements, and built-in functions. We discuss relevant programming issues of these features, including the object-oriented description of molecular interactions with molecule encapsulation, message passing, and the description of heterogeneity and anisotropy at the cell and molecule levels. By enabling the integration of modeling at the molecular level with system behavior at cell, tissue, organ, or even organism levels, the program will help improve our understanding of how complex and dynamic biological activities are generated and controlled by parallel functioning of molecular networks. Index Terms-Cellular automata, modeling, molecular network, object-oriented.

Prediction of anticancer activity of diterpenes isolated from the paraiban flora through a PLS model and molecular surfaces.

PubMed

Scotti, Luciana; Scotti, Marcus T; Ishiki, Hamilton; Junior, Francisco J B M; dos, Santos Paula F; Tavares, Josean F; da Silva, Marcelo S

2014-05-01

The aim of this work was to predict the anticancer potential of 3 atisane, and 3 trachylobane diterpene compounds extracted from the roots of Xylopia langsdorffiana. The prediction of anticancer activity as expressed against PC-3 tumor cells was made using a PLS model built with 26 diterpenes in the training set. Significant statistical measures were obtained. The six investigated diterpenes were applied to the model and their activities against PC-3 cells were calculated. All the diterpenes were active, with atisane diterpenes showing the higher pICso values. In human prostate carcinoma PC-3 cells, the apoptosis mechanism is related to an inhibition of IKK/NF-KB. Antioxidant potential implies a greater electronic molecular atmosphere (increased donor electron capacity), which can reduce radical reactivity, and facilitate post donation charge accommodation. Molecular surfaces indicated a much greater electronic cloud over atisane diterpenes.

Design of Novel Chemotherapeutic Agents Targeting Checkpoint Kinase 1 Using 3D-QSAR Modeling and Molecular Docking Methods.

PubMed

Balupuri, Anand; Balasubramanian, Pavithra K; Cho, Seung J

2016-01-01

Checkpoint kinase 1 (Chk1) has emerged as a potential therapeutic target for design and development of novel anticancer drugs. Herein, we have performed three-dimensional quantitative structure-activity relationship (3D-QSAR) and molecular docking analyses on a series of diazacarbazoles to design potent Chk1 inhibitors. 3D-QSAR models were developed using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. Docking studies were performed using AutoDock. The best CoMFA and CoMSIA models exhibited cross-validated correlation coefficient (q2) values of 0.631 and 0.585, and non-cross-validated correlation coefficient (r2) values of 0.933 and 0.900, respectively. CoMFA and CoMSIA models showed reasonable external predictabilities (r2 pred) of 0.672 and 0.513, respectively. A satisfactory performance in the various internal and external validation techniques indicated the reliability and robustness of the best model. Docking studies were performed to explore the binding mode of inhibitors inside the active site of Chk1. Molecular docking revealed that hydrogen bond interactions with Lys38, Glu85 and Cys87 are essential for Chk1 inhibitory activity. The binding interaction patterns observed during docking studies were complementary to 3D-QSAR results. Information obtained from the contour map analysis was utilized to design novel potent Chk1 inhibitors. Their activities and binding affinities were predicted using the derived model and docking studies. Designed inhibitors were proposed as potential candidates for experimental synthesis.

Molecular modeling-driven approach for identification of Janus kinase 1 inhibitors through 3D-QSAR, docking and molecular dynamics simulations.

PubMed

Itteboina, Ramesh; Ballu, Srilata; Sivan, Sree Kanth; Manga, Vijjulatha

2017-10-01

Janus kinase 1 (JAK 1) belongs to the JAK family of intracellular nonreceptor tyrosine kinase. JAK-signal transducer and activator of transcription (JAK-STAT) pathway mediate signaling by cytokines, which control survival, proliferation and differentiation of a variety of cells. Three-dimensional quantitative structure activity relationship (3 D-QSAR), molecular docking and molecular dynamics (MD) methods was carried out on a dataset of Janus kinase 1(JAK 1) inhibitors. Ligands were constructed and docked into the active site of protein using GLIDE 5.6. Best docked poses were selected after analysis for further 3 D-QSAR analysis using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methodology. Employing 60 molecules in the training set, 3 D-QSAR models were generate that showed good statistical reliability, which is clearly observed in terms of r 2 ncv and q 2 loo values. The predictive ability of these models was determined using a test set of 25 molecules that gave acceptable predictive correlation (r 2 Pred ) values. The key amino acid residues were identified by means of molecular docking, and the stability and rationality of the derived molecular conformations were also validated by MD simulation. The good consonance between the docking results and CoMFA/CoMSIA contour maps provides helpful clues about the reasonable modification of molecules in order to design more efficient JAK 1 inhibitors. The developed models are expected to provide some directives for further synthesis of highly effective JAK 1 inhibitors.

Reasoning with Atomic-Scale Molecular Dynamic Models

ERIC Educational Resources Information Center

Pallant, Amy; Tinker, Robert F.

2004-01-01

The studies reported in this paper are an initial effort to explore the applicability of computational models in introductory science learning. Two instructional interventions are described that use a molecular dynamics model embedded in a set of online learning activities with middle and high school students in 10 classrooms. The studies indicate…

Synthesis, QSAR, and Molecular Dynamics Simulation of Amidino-substituted Benzimidazoles as Dipeptidyl Peptidase III Inhibitors.

PubMed

Rastija, Vesna; Agić, Dejan; Tomiš, Sanja; Nikolič, Sonja; Hranjec, Marijana; Grace, Karminski-Zamola; Abramić, Marija

2015-01-01

A molecular modeling study is performed on series of benzimidazol-based inhibitors of human dipeptidyl peptidase III (DPP III). An eight novel compounds were synthesized in excellent yields using green chemistry approach. This study is aimed to elucidate the structural features of benzimidazole derivatives required for antagonism of human DPP III activity using Quantitative Structure-Activity Relationship (QSAR) analysis, and to understand the mechanism of one of the most potent inhibitor binding into the active site of this enzyme, by molecular dynamics (MD) simulations. The best model obtained includes S3K and RDF045m descriptors which have explained 89.4 % of inhibitory activity. Depicted moiety for strong inhibition activity matches to the structure of most potent compound. MD simulation has revealed importance of imidazolinyl and phenyl groups in the mechanism of binding into the active site of human DPP III.

Alignment-independent technique for 3D QSAR analysis

NASA Astrophysics Data System (ADS)

Wilkes, Jon G.; Stoyanova-Slavova, Iva B.; Buzatu, Dan A.

2016-04-01

Molecular biochemistry is controlled by 3D phenomena but structure-activity models based on 3D descriptors are infrequently used for large data sets because of the computational overhead for determining molecular conformations. A diverse dataset of 146 androgen receptor binders was used to investigate how different methods for defining molecular conformations affect the performance of 3D-quantitative spectral data activity relationship models. Molecular conformations tested: (1) global minimum of molecules' potential energy surface; (2) alignment-to-templates using equal electronic and steric force field contributions; (3) alignment using contributions "Best-for-Each" template; (4) non-energy optimized, non-aligned (2D > 3D). Aggregate predictions from models were compared. Highest average coefficients of determination ranged from R Test 2 = 0.56 to 0.61. The best model using 2D > 3D (imported directly from ChemSpider) produced R Test 2 = 0.61. It was superior to energy-minimized and conformation-aligned models and was achieved in only 3-7 % of the time required using the other conformation strategies. Predictions averaged from models built on different conformations achieved a consensus R Test 2 = 0.65. The best 2D > 3D model was analyzed for underlying structure-activity relationships. For the compound strongest binding to the androgen receptor, 10 substructural features contributing to binding were flagged. Utility of 2D > 3D was compared for two other activity endpoints, each modeling a medium sized data set. Results suggested that large scale, accurate predictions using 2D > 3D SDAR descriptors may be produced for interactions involving endocrine system nuclear receptors and other data sets in which strongest activities are produced by fairly inflexible substrates.

Postdoctoral Fellow | Center for Cancer Research

Cancer.gov

The Neural Development Section (NDS) headed by Dr. Lino Tessarollo has an open postdoctoral fellow position. The candidate should have a background in neurobiology and basic expertise in molecular biology, cell biology, immunoistochemistry and biochemistry.  Experience in confocal analysis is desired. The NDS study the biology of neurotrophin and Trk receptors function by using both in vitro and in vivo approaches. Our group makes extensive use of engineered mouse models and cell culture models. The current research emphasis is on understanding the molecular mechanisms by which activated trk receptor function. Specifically, we are dissecting the molecular mechanism responsible for modulating Trk receptors activity, including their interaction with specific scaffold proteins and proteins leading to de-activation of Trk signaling. Moreover, we are attempting to identify new signaling pathways activated by truncated Trk receptors.

Quantitative Structure-Activity Relationship Modeling Coupled with Molecular Docking Analysis in Screening of Angiotensin I-Converting Enzyme Inhibitory Peptides from Qula Casein Hydrolysates Obtained by Two-Enzyme Combination Hydrolysis.

PubMed

Lin, Kai; Zhang, Lanwei; Han, Xue; Meng, Zhaoxu; Zhang, Jianming; Wu, Yifan; Cheng, Dayou

2018-03-28

In this study, Qula casein derived from yak milk casein was hydrolyzed using a two-enzyme combination approach, and high angiotensin I-converting enzyme (ACE) inhibitory activity peptides were screened by quantitative structure-activity relationship (QSAR) modeling integrated with molecular docking analysis. Hydrolysates (<3 kDa) derived from combinations of thermolysin + alcalase and thermolysin + proteinase K demonstrated high ACE inhibitory activities. Peptide sequences in hydrolysates derived from these two combinations were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). On the basis of the QSAR modeling prediction, a total of 16 peptides were selected for molecular docking analysis. The docking study revealed that four of the peptides (KFPQY, MPFPKYP, MFPPQ, and QWQVL) bound the active site of ACE. These four novel peptides were chemically synthesized, and their IC 50 was determined. Among these peptides, KFPQY showed the highest ACE inhibitory activity (IC 50 = 12.37 ± 0.43 μM). Our study indicated that Qula casein presents an excellent source to produce ACE inhibitory peptides.

A multiscale computational approach to dissect early events in the Erb family receptor mediated activation, differential signaling, and relevance to oncogenic transformations.

PubMed

Liu, Yingting; Purvis, Jeremy; Shih, Andrew; Weinstein, Joshua; Agrawal, Neeraj; Radhakrishnan, Ravi

2007-06-01

We describe a hierarchical multiscale computational approach based on molecular dynamics simulations, free energy-based molecular docking simulations, deterministic network-based kinetic modeling, and hybrid discrete/continuum stochastic dynamics protocols to study the dimer-mediated receptor activation characteristics of the Erb family receptors, specifically the epidermal growth factor receptor (EGFR). Through these modeling approaches, we are able to extend the prior modeling of EGF-mediated signal transduction by considering specific EGFR tyrosine kinase (EGFRTK) docking interactions mediated by differential binding and phosphorylation of different C-terminal peptide tyrosines on the RTK tail. By modeling signal flows through branching pathways of the EGFRTK resolved on a molecular basis, we are able to transcribe the effects of molecular alterations in the receptor (e.g., mutant forms of the receptor) to differing kinetic behavior and downstream signaling response. Our molecular dynamics simulations show that the drug sensitizing mutation (L834R) of EGFR stabilizes the active conformation to make the system constitutively active. Docking simulations show preferential characteristics (for wildtype vs. mutant receptors) in inhibitor binding as well as preferential enhancement of phosphorylation of particular substrate tyrosines over others. We find that in comparison to the wildtype system, the L834R mutant RTK preferentially binds the inhibitor erlotinib, as well as preferentially phosphorylates the substrate tyrosine Y1068 but not Y1173. We predict that these molecular level changes result in preferential activation of the Akt signaling pathway in comparison to the Erk signaling pathway for cells with normal EGFR expression. For cells with EGFR over expression, the mutant over activates both Erk and Akt pathways, in comparison to wildtype. These results are consistent with qualitative experimental measurements reported in the literature. We discuss these consequences in light of how the network topology and signaling characteristics of altered (mutant) cell lines are shaped differently in relationship to native cell lines.

Toward the identification of a reliable 3D-QSAR model for the protein tyrosine phosphatase 1B inhibitors

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.

A ligand-based comparative molecular field analysis (CoMFA) and homology model based molecular docking studies on 3', 4'-dihydroxyflavones as rat 5-lipoxygenase inhibitors: Design of new inhibitors.

PubMed

Ahamed, T K Shameera; Muraleedharan, K

2017-12-01

In this study, ligand based comparative molecular field analysis (CoMFA) with five principal components was performed on class of 3', 4'-dihydroxyflavone derivatives for potent rat 5-LOX inhibitors. The percentage contributions in building of CoMFA model were 91.36% for steric field and 8.6% for electrostatic field. R 2 values for training and test sets were found to be 0.9320 and 0.8259, respectively. In case of LOO, LTO and LMO cross validation test, q 2 values were 0.6587, 0.6479 and 0.5547, respectively. These results indicate that the model has high statistical reliability and good predictive power. The extracted contour maps were used to identify the important regions where the modification was necessary to design a new molecule with improved activity. The study has developed a homology model for rat 5-LOX and recognized the key residues at the binding site. Docking of most active molecule to the binding site of 5-LOX confirmed the stability and rationality of CoMFA model. Based on molecular docking results and CoMFA contour plots, new inhibitors with higher activity with respect to the most active compound in data set were designed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Structure-Activity Relationship Studies and Molecular Modeling of Naphthalene-Based Sphingosine Kinase 2 Inhibitors.

PubMed

Congdon, Molly D; Kharel, Yugesh; Brown, Anne M; Lewis, Stephanie N; Bevan, David R; Lynch, Kevin R; Santos, Webster L

2016-03-10

The two isoforms of sphingosine kinase (SphK1 and SphK2) are the only enzymes that phosphorylate sphingosine to sphingosine-1-phosphate (S1P), which is a pleiotropic lipid mediator involved in a broad range of cellular processes including migration, proliferation, and inflammation. SphKs are targets for various diseases such as cancer, fibrosis, and Alzheimer's and sickle cell disease. Herein, we disclose the structure-activity profile of naphthalene-containing SphK inhibitors and molecular modeling studies that reveal a key molecular switch that controls SphK selectivity.

Molecular properties of steroids involved in their effects on the biophysical state of membranes.

PubMed

Wenz, Jorge J

2015-10-01

The activity of steroids on membranes was studied in relation to their ordering, rigidifying, condensing and/or raft promoting ability. The structures of 82 steroids were modeled by a semi-empirical procedure (AM1) and 245 molecular descriptors were next computed on the optimized energy conformations. Principal component analysis, mean contrasting and logistic regression were used to correlate the molecular properties with 212 cases of documented activities. It was possible to group steroids based on their properties and activities, indicating that steroids having similar molecular properties have similar activities on membranes. Steroids having high values of area, partition coefficient, volume, number of rotatable bonds, molar refractivity, polarizability or mass displayed ordering, rigidifying, condensing and/or raft promoting activity on membranes higher than those steroids having low values in such molecular properties. After a variable selection procedure circumventing correlation problems among descriptors, area and log P were found as the most relevant properties in governing and predicting the activity of steroids on membranes. A logistic regression model as a function of the area and log P of the steroids is proposed, which is able to predict correctly 92.5% of the cases. A rationale of the findings is discussed. Copyright © 2015 Elsevier B.V. All rights reserved.

Scaffolding Students' Online Critiquing of Expert- and Peer-generated Molecular Models of Chemical Reactions

NASA Astrophysics Data System (ADS)

Chang, Hsin-Yi; Chang, Hsiang-Chi

2013-08-01

In this study, we developed online critiquing activities using an open-source computer learning environment. We investigated how well the activities scaffolded students to critique molecular models of chemical reactions made by scientists, peers, and a fictitious peer, and whether the activities enhanced the students' understanding of science models and chemical reactions. The activities were implemented in an eighth-grade class with 28 students in a public junior high school in southern Taiwan. The study employed mixed research methods. Data collected included pre- and post-instructional assessments, post-instructional interviews, and students' electronic written responses and oral discussions during the critiquing activities. The results indicated that these activities guided the students to produce overall quality critiques. Also, the students developed a more sophisticated understanding of chemical reactions and scientific models as a result of the intervention. Design considerations for effective model critiquing activities are discussed based on observational results, including the use of peer-generated artefacts for critiquing to promote motivation and collaboration, coupled with critiques of scientific models to enhance students' epistemological understanding of model purpose and communication.

Multifunctional receptor model for dioxin and related compound toxic action: possible thyroid hormone-responsive effector-linked site.

PubMed Central

McKinney, J D

1989-01-01

Molecular/theoretical modeling studies have revealed that thyroid hormones and toxic chlorinated aromatic hydrocarbons of environmental significance (for which dioxin or TCDD is the prototype) have similar structural properties that could be important in molecular recognition in biochemical systems. These molecular properties include a somewhat rigid, sterically accessible and polarizable aromatic ring and size-limited, hydrophobic lateral substituents, usually contained in opposite adjoining rings of a diphenyl compound. These molecular properties define the primary binding groups thought to be important in molecular recognition of both types of structures in biochemical systems. Similar molecular reactivities are supported by the demonstration of effective specific binding of thyroid hormones and chlorinated aromatic hydrocarbons with four different proteins, enzymes, or receptor preparations that are known or suspected to be involved in the expression of thyroid hormone activity. These binding interactions represent both aromatic-aromatic (stacking) and molecular cleft-type recognition processes. A multiple protein or multifunctional receptor-ligand binding mechanism model is proposed as a way of visualizing the details and possible role of both the stacking and cleft type molecular recognition factors in the expression of biological activity. The model suggests a means by which hormone-responsive effector-linked sites (possible protein-protein-DNA complexes) can maintain highly structurally specific control of hormone action. Finally, the model also provides a theoretical basis for the design and conduct of further biological experimentation on the molecular mechanism(s) of action of toxic chlorinated aromatic hydrocarbons and thyroid hormones. Images FIGURE 3. A FIGURE 3. B FIGURE 3. C FIGURE 3. D PMID:2551666

Use of Molecular Models for Active Learning in Biochemistry Lecture Courses

ERIC Educational Resources Information Center

Hageman, James H.

2010-01-01

The pedagogical value of having biochemistry and organic chemistry students build and manipulate physical models of chemical species is well established in the literature. Nevertheless, for the most part, the use of molecular models is generally limited to several laboratory exercises or to demonstrations in the classroom setting. A simple…

Manipulating 3D-Printed and Paper Models Enhances Student Understanding of Viral Replication

ERIC Educational Resources Information Center

Couper, Lisa; Johannes, Kristen; Powers, Jackie; Silberglitt, Matt; Davenport, Jodi

2016-01-01

Understanding key concepts in molecular biology requires reasoning about molecular processes that are not directly observable and, as such, presents a challenge to students and teachers. We ask whether novel interactive physical models and activities can help students understand key processes in viral replication. Our 3D tangible models are…

Mean ionic activity coefficients in aqueous NaCl solutions from molecular dynamics simulations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mester, Zoltan; Panagiotopoulos, Athanassios Z., E-mail: azp@princeton.edu

The mean ionic activity coefficients of aqueous NaCl solutions of varying concentrations at 298.15 K and 1 bar have been obtained from molecular dynamics simulations by gradually turning on the interactions of an ion pair inserted into the solution. Several common non-polarizable water and ion models have been used in the simulations. Gibbs-Duhem equation calculations of the thermodynamic activity of water are used to confirm the thermodynamic consistency of the mean ionic activity coefficients. While the majority of model combinations predict the correct trends in mean ionic activity coefficients, they overestimate their values at high salt concentrations. The solubility predictionsmore » also suffer from inaccuracies, with all models underpredicting the experimental values, some by large factors. These results point to the need for further ion and water model development.« less

Comparison of 3D quantitative structure-activity relationship methods: Analysis of the in vitro antimalarial activity of 154 artemisinin analogues by hypothetical active-site lattice and comparative molecular field analysis

NASA Astrophysics Data System (ADS)

Woolfrey, John R.; Avery, Mitchell A.; Doweyko, Arthur M.

1998-03-01

Two three-dimensional quantitative structure-activity relationship (3D-QSAR) methods, comparative molecular field analysis (CoMFA) and hypothetical active site lattice (HASL), were compared with respect to the analysis of a training set of 154 artemisinin analogues. Five models were created, including a complete HASL and two trimmed versions, as well as two CoMFA models (leave-one-out standard CoMFA and the guided-region selection protocol). Similar r2 and q2 values were obtained by each method, although some striking differences existed between CoMFA contour maps and the HASL output. Each of the four predictive models exhibited a similar ability to predict the activity of a test set of 23 artemisinin analogues, although some differences were noted as to which compounds were described well by either model.

Molecular docking and QSAR study on steroidal compounds as aromatase inhibitors.

PubMed

Dai, Yujie; Wang, Qiang; Zhang, Xiuli; Jia, Shiru; Zheng, Heng; Feng, Dacheng; Yu, Peng

2010-12-01

In order to develop more potent, selective and less toxic steroidal aromatase (AR) inhibitors, molecular docking, 2D and 3D hybrid quantitative structure-activity relationship (QSAR) study have been conducted using topological, molecular shape, spatial, structural and thermodynamic descriptors on 32 steroidal compounds. The molecular docking study shows that one or more hydrogen bonds with MET374 are one of the essential requirements for the optimum binding of ligands. The QSAR model obtained indicates that the aromatase inhibitory activity can be enhanced by increasing SIC, SC_3_C, Jurs_WNSA_1, Jurs_WPSA_1 and decreasing CDOCKER interaction energy (ECD), IAC_Total and Shadow_XZfrac. The predicted results shows that this model has a comparatively good predictive power which can be used in prediction of activity of new steroidal aromatase inhibitors. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

A log-normal distribution model for the molecular weight of aquatic fulvic acids

USGS Publications Warehouse

Cabaniss, S.E.; Zhou, Q.; Maurice, P.A.; Chin, Y.-P.; Aiken, G.R.

2000-01-01

The molecular weight of humic substances influences their proton and metal binding, organic pollutant partitioning, adsorption onto minerals and activated carbon, and behavior during water treatment. We propose a lognormal model for the molecular weight distribution in aquatic fulvic acids to provide a conceptual framework for studying these size effects. The normal curve mean and standard deviation are readily calculated from measured M(n) and M(w) and vary from 2.7 to 3 for the means and from 0.28 to 0.37 for the standard deviations for typical aquatic fulvic acids. The model is consistent with several types of molecular weight data, including the shapes of high- pressure size-exclusion chromatography (HP-SEC) peaks. Applications of the model to electrostatic interactions, pollutant solubilization, and adsorption are explored in illustrative calculations.The molecular weight of humic substances influences their proton and metal binding, organic pollutant partitioning, adsorption onto minerals and activated carbon, and behavior during water treatment. We propose a log-normal model for the molecular weight distribution in aquatic fulvic acids to provide a conceptual framework for studying these size effects. The normal curve mean and standard deviation are readily calculated from measured Mn and Mw and vary from 2.7 to 3 for the means and from 0.28 to 0.37 for the standard deviations for typical aquatic fulvic acids. The model is consistent with several type's of molecular weight data, including the shapes of high-pressure size-exclusion chromatography (HP-SEC) peaks. Applications of the model to electrostatic interactions, pollutant solubilization, and adsorption are explored in illustrative calculations.

Analogs of methyllycaconitine as novel noncompetitive inhibitors of nicotinic receptors: pharmacological characterization, computational modeling, and pharmacophore development.

PubMed

McKay, Dennis B; Chang, Cheng; González-Cestari, Tatiana F; McKay, Susan B; El-Hajj, Raed A; Bryant, Darrell L; Zhu, Michael X; Swaan, Peter W; Arason, Kristjan M; Pulipaka, Aravinda B; Orac, Crina M; Bergmeier, Stephen C

2007-05-01

As a novel approach to drug discovery involving neuronal nicotinic acetylcholine receptors (nAChRs), our laboratory targeted nonagonist binding sites (i.e., noncompetitive binding sites, negative allosteric binding sites) located on nAChRs. Cultured bovine adrenal cells were used as neuronal models to investigate interactions of 67 analogs of methyllycaconitine (MLA) on native alpha3beta4* nAChRs. The availability of large numbers of structurally related molecules presents a unique opportunity for the development of pharmacophore models for noncompetitive binding sites. Our MLA analogs inhibited nicotine-mediated functional activation of both native and recombinant alpha3beta4* nAChRs with a wide range of IC(50) values (0.9-115 microM). These analogs had little or no inhibitory effects on agonist binding to native or recombinant nAChRs, supporting noncompetitive inhibitory activity. Based on these data, two highly predictive 3D quantitative structure-activity relationship (comparative molecular field analysis and comparative molecular similarity index analysis) models were generated. These computational models were successfully validated and provided insights into the molecular interactions of MLA analogs with nAChRs. In addition, a pharmacophore model was constructed to analyze and visualize the binding requirements to the analog binding site. The pharmacophore model was subsequently applied to search structurally diverse molecular databases to prospectively identify novel inhibitors. The rapid identification of eight molecules from database mining and our successful demonstration of in vitro inhibitory activity support the utility of these computational models as novel tools for the efficient retrieval of inhibitors. These results demonstrate the effectiveness of computational modeling and pharmacophore development, which may lead to the identification of new therapeutic drugs that target novel sites on nAChRs.

[Comparison study on adsorption of middle molecular substances with multiwalled carbon nanotubes and activated carbon].

PubMed

Li, Guifeng; Wan, Jianxin; Huang, Xiangqian; Zeng, Qiao; Tang, Jing

2011-08-01

In recent years, multi-walled carbon nanotubes (MWCTs) are very favorable to the adsorption of middle molecular substances in the hemoperfusion because of their multiporous structure, large surface area and high reactivity, which are beneficial to the excellent absorption properties. The purpose of this study was to study the MWCTs on the adsorption capacity of the middle molecular substances. Vitamin B12 (VB12) was selected as a model of the middle molecular substances. The morphologies of MWCTs and activated carbon from commercial "carbon kidney" were observed with scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The adsorption behavior of VB12 was compared to each other with UV-visible absorption spectra. The MWCTs formed a sophistaicate gap structure, and compared to the activated carbon, MWCTs had a larger surface area. By Langmuir equation and Freundlich equation fitting analysis, VB12 adsorption on MWCTs is fit for multi-molecular layer adsorption, and the adsorption type of activated carbon is more inclined to the model corresponding to Langmuir monolayer adsorption. The adsorption rate of MWCTs is faster than that of the activated carbon and the adsorption capacity is greater, which could be expected to become the new adsorbent in the hemoperfusion.

Design, synthesis, molecular modeling and biological evaluation of novel 2,3-dihydrophthalazine-1,4-dione derivatives as potential anticonvulsant agents

NASA Astrophysics Data System (ADS)

El-Helby, Abdel Ghany A.; Ayyad, Rezk R.; Sakr, Helmy M.; Abdelrahim, Adel S.; El-Adl, K.; Sherbiny, Farag S.; Eissa, Ibrahim H.; Khalifa, Mohamed M.

2017-02-01

In view of their expected anticonvulsant activity, some novel derivatives of 2,3-dihydrophthalazine-1,4-dione 4-22 were designed, synthesized and evaluated using pentylenetetrazole (PTZ) and picrotoxin as convulsion-inducing models. Moreover, the most active compounds were tested against electrical induced convulsion using maximal electroshock (MES) models of seizures. Most of the tested compounds showed considerable anticonvulsant activity in at least one of the anticonvulsant tests. Compounds 13 and 14g were proved to be the most potent compounds of this series with relatively low toxicity in the median lethal dose test when compared with the reference drug. Molecular modeling studies were done to verify the biological activity. The obtained results showed that the most potent compounds could be useful as a template for future design, optimization, and investigation to produce more active analogues.

3D-QSAR modeling and molecular docking studies on a series of 2,5 disubstituted 1,3,4-oxadiazoles

NASA Astrophysics Data System (ADS)

Ghaleb, Adib; Aouidate, Adnane; Ghamali, Mounir; Sbai, Abdelouahid; Bouachrine, Mohammed; Lakhlifi, Tahar

2017-10-01

3D-QSAR (comparative molecular field analysis (CoMFA)) and comparative molecular similarity indices analysis (CoMSIA) were performed on novel 2,5 disubstituted 1,3,4-oxadiazoles analogues as anti-fungal agents. The CoMFA and CoMSIA models using 13 compounds in the training set gives Q2 values of 0.52 and 0.51 respectively, while R2 values of 0.92. The adapted alignment method with the suitable parameters resulted in reliable models. The contour maps produced by the CoMFA and CoMSIA models were employed to determine a three-dimensional quantitative structure-activity relationship. Based on this study a set of new molecules with high predicted activities were designed. Surflex-docking confirmed the stability of predicted molecules in the receptor.

Investigation of oxygen self-diffusion in PuO 2 by combining molecular dynamics with thermodynamic calculations

DOE PAGES

Saltas, V.; Chroneos, A.; Cooper, Michael William D.; ...

2016-01-01

In the present work, the defect properties of oxygen self-diffusion in PuO 2 are investigated over a wide temperature (300–1900 K) and pressure (0–10 GPa) range, by combining molecular dynamics simulations and thermodynamic calculations. Based on the well-established cBΩ thermodynamic model which connects the activation Gibbs free energy of diffusion with the bulk elastic and expansion properties, various point defect parameters such as activation enthalpy, activation entropy, and activation volume were calculated as a function of T and P. Molecular dynamics calculations provided the necessary bulk properties for the proper implementation of the thermodynamic model, in the lack of anymore » relevant experimental data. The estimated compressibility and the thermal expansion coefficient of activation volume are found to be more than one order of magnitude greater than the corresponding values of the bulk plutonia. As a result, the diffusion mechanism is discussed in the context of the temperature and pressure dependence of the activation volume.« less

Predicting Biological Information Flow in a Model Oxygen Minimum Zone

NASA Astrophysics Data System (ADS)

Louca, S.; Hawley, A. K.; Katsev, S.; Beltran, M. T.; Bhatia, M. P.; Michiels, C.; Capelle, D.; Lavik, G.; Doebeli, M.; Crowe, S.; Hallam, S. J.

2016-02-01

Microbial activity drives marine biochemical fluxes and nutrient cycling at global scales. Geochemical measurements as well as molecular techniques such as metagenomics, metatranscriptomics and metaproteomics provide great insight into microbial activity. However, an integration of molecular and geochemical data into mechanistic biogeochemical models is still lacking. Recent work suggests that microbial metabolic pathways are, at the ecosystem level, strongly shaped by stoichiometric and energetic constraints. Hence, models rooted in fluxes of matter and energy may yield a holistic understanding of biogeochemistry. Furthermore, such pathway-centric models would allow a direct consolidation with meta'omic data. Here we present a pathway-centric biogeochemical model for the seasonal oxygen minimum zone in Saanich Inlet, a fjord off the coast of Vancouver Island. The model considers key dissimilatory nitrogen and sulfur fluxes, as well as the population dynamics of the genes that mediate them. By assuming a direct translation of biocatalyzed energy fluxes to biosynthesis rates, we make predictions about the distribution and activity of the corresponding genes. A comparison of the model to molecular measurements indicates that the model explains observed DNA, RNA, protein and cell depth profiles. This suggests that microbial activity in marine ecosystems such as oxygen minimum zones is well described by DNA abundance, which, in conjunction with geochemical constraints, determines pathway expression and process rates. Our work further demonstrates how meta'omic data can be mechanistically linked to environmental redox conditions and biogeochemical processes.

Rational design of methicillin resistance staphylococcus aureus inhibitors through 3D-QSAR, molecular docking and molecular dynamics simulations.

PubMed

Ballu, Srilata; Itteboina, Ramesh; Sivan, Sree Kanth; Manga, Vijjulatha

2018-04-01

Staphylococcus aureus is a gram positive bacterium. It is the leading cause of skin and respiratory infections, osteomyelitis, Ritter's disease, endocarditis, and bacteraemia in the developed world. We employed combined studies of 3D QSAR, molecular docking which are validated by molecular dynamics simulations and in silico ADME prediction have been performed on Isothiazoloquinolones inhibitors against methicillin resistance Staphylococcus aureus. Three-dimensional quantitative structure-activity relationship (3D-QSAR) study was applied using comparative molecular field analysis (CoMFA) with Q 2 of 0.578, R 2 of 0.988, and comparative molecular similarity indices analysis (CoMSIA) with Q 2 of 0.554, R 2 of 0.975. The predictive ability of these model was determined using a test set of molecules that gave acceptable predictive correlation (r 2 Pred) values 0.55 and 0.57 of CoMFA and CoMSIA respectively. Docking, simulations were employed to position the inhibitors into protein active site to find out the most probable binding mode and most reliable conformations. Developed models and Docking methods provide guidance to design molecules with enhanced activity. Copyright © 2017 Elsevier Ltd. All rights reserved.

QSAR Analysis of 2-Amino or 2-Methyl-1-Substituted Benzimidazoles Against Pseudomonas aeruginosa

PubMed Central

Podunavac-Kuzmanović, Sanja O.; Cvetković, Dragoljub D.; Barna, Dijana J.

2009-01-01

A set of benzimidazole derivatives were tested for their inhibitory activities against the Gram-negative bacterium Pseudomonas aeruginosa and minimum inhibitory concentrations were determined for all the compounds. Quantitative structure activity relationship (QSAR) analysis was applied to fourteen of the abovementioned derivatives using a combination of various physicochemical, steric, electronic, and structural molecular descriptors. A multiple linear regression (MLR) procedure was used to model the relationships between molecular descriptors and the antibacterial activity of the benzimidazole derivatives. The stepwise regression method was used to derive the most significant models as a calibration model for predicting the inhibitory activity of this class of molecules. The best QSAR models were further validated by a leave one out technique as well as by the calculation of statistical parameters for the established theoretical models. To confirm the predictive power of the models, an external set of molecules was used. High agreement between experimental and predicted inhibitory values, obtained in the validation procedure, indicated the good quality of the derived QSAR models. PMID:19468332

Molecular design of new aggrecanases-2 inhibitors.

PubMed

Shan, Zhi Jie; Zhai, Hong Lin; Huang, Xiao Yan; Li, Li Na; Zhang, Xiao Yun

2013-10-01

Aggrecanases-2 is a very important potential drug target for the treatment of osteoarthritis. In this study, a series of known aggrecanases-2 inhibitors was analyzed by the technologies of three-dimensional quantitative structure-activity relationships (3D-QSAR) and molecular docking. Two 3D-QSAR models, which based on comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) methods, were established. Molecular docking was employed to explore the details of the interaction between inhibitors and aggrecanases-2 protein. According to the analyses for these models, several new potential inhibitors with higher activity predicted were designed, and were supported by the simulation of molecular docking. This work propose the fast and effective approach to design and prediction for new potential inhibitors, and the study of the interaction mechanism provide a better understanding for the inhibitors binding into the target protein, which will be useful for the structure-based drug design and modifications. Copyright © 2013 Elsevier Ltd. All rights reserved.

Molecular Modeling and Experimental Study of Nonlinear Optical Compounds: Mono-Substituted Derivatives of Dicyanovinylbenzene

NASA Technical Reports Server (NTRS)

Timofeeva, Tatyana V.; Nesterov, Vladimir N.; Antipin, Mikhael Y.; Clark, R. D.; Sanghadasa, M.; Cardelino, B. H.; Moore, C. E.; Frazier, Donald O.

2000-01-01

A search for potential nonlinear optical (NLO) compounds has been performed using the Cambridge Structural Database and molecular modeling. We have studied a series of mono-substituted derivatives of dicyanovinylbenzene as the NLO properties of one of its derivatives (o-methoxy-dicyanovinylbenzene, DIVA) were described earlier. The molecular geometry in the series of the compounds studied was investigated with an X- ray analysis and discussed along with results of molecular mechanics and ab initio quantum chemical calculations. The influence of crystal packing on the molecular planarity has been revealed. Two new compounds from the series studied were found to be active for second harmonic generation (SHG) in the powder. The measurements of SHG efficiency have shown that the o-F- and p-Cl-derivatives of dicyanovinylbenzene are about 10 and 20- times more active than urea, respectively. The peculiarities of crystal structure formation in the framework of balance between the van der Waals and electrostatic interactions have been discussed. The crystal morphology of DIVA and two new SHG-active compounds have been calculated on the basis of their known crystal structures.

Antimicrobial and anticancer activity of some novel fluorinated thiourea derivatives carrying sulfonamide moieties: synthesis, biological evaluation and molecular docking.

PubMed

Ghorab, Mostafa M; Alsaid, Mansour S; El-Gaby, Mohamed S A; Elaasser, Mahmoud M; Nissan, Yassin M

2017-04-07

Various thiourea derivatives have been used as starting materials for compounds with better biological activities. Molecular modeling tools are used to explore their mechanism of action. A new series of thioureas were synthesized. Fluorinated pyridine derivative 4a showed the highest antimicrobial activity (with MIC values ranged from 1.95 to 15.63 µg/mL). Interestingly, thiadiazole derivative 4c and coumarin derivative 4d exhibited selective antibacterial activities against Gram positive bacteria. Fluorinated pyridine derivative 4a was the most active against HepG2 with IC50 value of 4.8 μg/mL. Molecular docking was performed on the active site of MK-2 with good results. Novel compounds were obtained with good anticancer and antibacterial activity especially fluorinated pyridine derivative 4a and molecular docking study suggest good activity as mitogen activated protein kinase-2 inhibitor. Graphical abstract Compound 4a in the active site of MK-2.

Muscle activation described with a differential equation model for large ensembles of locally coupled molecular motors.

PubMed

Walcott, Sam

2014-10-01

Molecular motors, by turning chemical energy into mechanical work, are responsible for active cellular processes. Often groups of these motors work together to perform their biological role. Motors in an ensemble are coupled and exhibit complex emergent behavior. Although large motor ensembles can be modeled with partial differential equations (PDEs) by assuming that molecules function independently of their neighbors, this assumption is violated when motors are coupled locally. It is therefore unclear how to describe the ensemble behavior of the locally coupled motors responsible for biological processes such as calcium-dependent skeletal muscle activation. Here we develop a theory to describe locally coupled motor ensembles and apply the theory to skeletal muscle activation. The central idea is that a muscle filament can be divided into two phases: an active and an inactive phase. Dynamic changes in the relative size of these phases are described by a set of linear ordinary differential equations (ODEs). As the dynamics of the active phase are described by PDEs, muscle activation is governed by a set of coupled ODEs and PDEs, building on previous PDE models. With comparison to Monte Carlo simulations, we demonstrate that the theory captures the behavior of locally coupled ensembles. The theory also plausibly describes and predicts muscle experiments from molecular to whole muscle scales, suggesting that a micro- to macroscale muscle model is within reach.

Structure-activity relationships for serotonin transporter and dopamine receptor selectivity.

PubMed

Agatonovic-Kustrin, Snezana; Davies, Paul; Turner, Joseph V

2009-05-01

Antipsychotic medications have a diverse pharmacology with affinity for serotonergic, dopaminergic, adrenergic, histaminergic and cholinergic receptors. Their clinical use now also includes the treatment of mood disorders, thought to be mediated by serotonergic receptor activity. The aim of our study was to characterise the molecular properties of antipsychotic agents, and to develop a model that would indicate molecular specificity for the dopamine (D(2)) receptor and the serotonin (5-HT) transporter. Back-propagation artificial neural networks (ANNs) were trained on a dataset of 47 ligands categorically assigned antidepressant or antipsychotic utility. The structure of each compound was encoded with 63 calculated molecular descriptors. ANN parameters including hidden neurons and input descriptors were optimised based on sensitivity analyses, with optimum models containing between four and 14 descriptors. Predicted binding preferences were in excellent agreement with clinical antipsychotic or antidepressant utility. Validated models were further tested by use of an external prediction set of five drugs with unknown mechanism of action. The SAR models developed revealed the importance of simple molecular characteristics for differential binding to the D(2) receptor and the 5-HT transporter. These included molecular size and shape, solubility parameters, hydrogen donating potential, electrostatic parameters, stereochemistry and presence of nitrogen. The developed models and techniques employed are expected to be useful in the rational design of future therapeutic agents.

Star formation in evolving molecular clouds

NASA Astrophysics Data System (ADS)

Völschow, M.; Banerjee, R.; Körtgen, B.

2017-09-01

Molecular clouds are the principle stellar nurseries of our universe; they thus remain a focus of both observational and theoretical studies. From observations, some of the key properties of molecular clouds are well known but many questions regarding their evolution and star formation activity remain open. While numerical simulations feature a large number and complexity of involved physical processes, this plethora of effects may hide the fundamentals that determine the evolution of molecular clouds and enable the formation of stars. Purely analytical models, on the other hand, tend to suffer from rough approximations or a lack of completeness, limiting their predictive power. In this paper, we present a model that incorporates central concepts of astrophysics as well as reliable results from recent simulations of molecular clouds and their evolutionary paths. Based on that, we construct a self-consistent semi-analytical framework that describes the formation, evolution, and star formation activity of molecular clouds, including a number of feedback effects to account for the complex processes inside those objects. The final equation system is solved numerically but at much lower computational expense than, for example, hydrodynamical descriptions of comparable systems. The model presented in this paper agrees well with a broad range of observational results, showing that molecular cloud evolution can be understood as an interplay between accretion, global collapse, star formation, and stellar feedback.

Contributions of different degrees of freedom to thermal transport in the C60 molecular crystal

NASA Astrophysics Data System (ADS)

Kumar, Sushant; Shao, Cheng; Lu, Simon; McGaughey, Alan J. H.

2018-03-01

Three models of the C60 molecular crystal are studied using molecular dynamics simulations to resolve the roles played by intermolecular and intramolecular degrees of freedom (DOF) in its structural, mechanical, and thermal properties at temperatures between 35 and 400 K. In the full DOF model, all DOF are active. In the rigid body model, the intramolecular DOF are frozen, such that only center of mass (COM) translations and molecular rotations/librations are active. In the point mass model, the molecule is replaced by a point mass, such that only COM translations are active. The zero-pressure lattice constants and bulk moduli predicted from the three models fall within ranges of 0.15 and 20%. The thermal conductivity of the point mass model is the largest across the temperature range, showing a crystal-like temperature dependence (i.e., it decreases with increasing temperature) due to the presence of phonon modes associated with the COM translations. The rigid body model thermal conductivity is the smallest and follows two distinct regimes. It is crystal-like at low temperatures and becomes temperature invariant at high temperatures. The latter is typical of the behavior of an amorphous material. By calculating the rotational diffusion coefficient, the transition between the two regimes is found to occur at the temperature where the molecules begin to rotate freely. Above this temperature, phonons related to COM translations are scattered by the rotational DOF. The full DOF model thermal conductivity is larger than that of the rigid body model, indicating that intramolecular DOF contribute to thermal transport.

On the Relationship between Molecular Hit Rates in High-Throughput Screening and Molecular Descriptors.

PubMed

Hansson, Mari; Pemberton, John; Engkvist, Ola; Feierberg, Isabella; Brive, Lars; Jarvis, Philip; Zander-Balderud, Linda; Chen, Hongming

2014-06-01

High-throughput screening (HTS) is widely used in the pharmaceutical industry to identify novel chemical starting points for drug discovery projects. The current study focuses on the relationship between molecular hit rate in recent in-house HTS and four common molecular descriptors: lipophilicity (ClogP), size (heavy atom count, HEV), fraction of sp(3)-hybridized carbons (Fsp3), and fraction of molecular framework (f(MF)). The molecular hit rate is defined as the fraction of times the molecule has been assigned as active in the HTS campaigns where it has been screened. Beta-binomial statistical models were built to model the molecular hit rate as a function of these descriptors. The advantage of the beta-binomial statistical models is that the correlation between the descriptors is taken into account. Higher degree polynomial terms of the descriptors were also added into the beta-binomial statistic model to improve the model quality. The relative influence of different molecular descriptors on molecular hit rate has been estimated, taking into account that the descriptors are correlated to each other through applying beta-binomial statistical modeling. The results show that ClogP has the largest influence on the molecular hit rate, followed by Fsp3 and HEV. f(MF) has only a minor influence besides its correlation with the other molecular descriptors. © 2013 Society for Laboratory Automation and Screening.

Chemical Sensor Array Response Modeling Using Quantitative Structure-Activity Relationships Technique

NASA Astrophysics Data System (ADS)

Shevade, Abhijit V.; Ryan, Margaret A.; Homer, Margie L.; Zhou, Hanying; Manfreda, Allison M.; Lara, Liana M.; Yen, Shiao-Pin S.; Jewell, April D.; Manatt, Kenneth S.; Kisor, Adam K.

We have developed a Quantitative Structure-Activity Relationships (QSAR) based approach to correlate the response of chemical sensors in an array with molecular descriptors. A novel molecular descriptor set has been developed; this set combines descriptors of sensing film-analyte interactions, representing sensor response, with a basic analyte descriptor set commonly used in QSAR studies. The descriptors are obtained using a combination of molecular modeling tools and empirical and semi-empirical Quantitative Structure-Property Relationships (QSPR) methods. The sensors under investigation are polymer-carbon sensing films which have been exposed to analyte vapors at parts-per-million (ppm) concentrations; response is measured as change in film resistance. Statistically validated QSAR models have been developed using Genetic Function Approximations (GFA) for a sensor array for a given training data set. The applicability of the sensor response models has been tested by using it to predict the sensor activities for test analytes not considered in the training set for the model development. The validated QSAR sensor response models show good predictive ability. The QSAR approach is a promising computational tool for sensing materials evaluation and selection. It can also be used to predict response of an existing sensing film to new target analytes.

A network of molecular switches controls the activation of the two-component response regulator NtrC

NASA Astrophysics Data System (ADS)

Vanatta, Dan K.; Shukla, Diwakar; Lawrenz, Morgan; Pande, Vijay S.

2015-06-01

Recent successes in simulating protein structure and folding dynamics have demonstrated the power of molecular dynamics to predict the long timescale behaviour of proteins. Here, we extend and improve these methods to predict molecular switches that characterize conformational change pathways between the active and inactive state of nitrogen regulatory protein C (NtrC). By employing unbiased Markov state model-based molecular dynamics simulations, we construct a dynamic picture of the activation pathways of this key bacterial signalling protein that is consistent with experimental observations and predicts new mutants that could be used for validation of the mechanism. Moreover, these results suggest a novel mechanistic paradigm for conformational switching.

QSAR modeling of cumulative environmental end-points for the prioritization of hazardous chemicals.

PubMed

Gramatica, Paola; Papa, Ester; Sangion, Alessandro

2018-01-24

The hazard of chemicals in the environment is inherently related to the molecular structure and derives simultaneously from various chemical properties/activities/reactivities. Models based on Quantitative Structure Activity Relationships (QSARs) are useful to screen, rank and prioritize chemicals that may have an adverse impact on humans and the environment. This paper reviews a selection of QSAR models (based on theoretical molecular descriptors) developed for cumulative multivariate endpoints, which were derived by mathematical combination of multiple effects and properties. The cumulative end-points provide an integrated holistic point of view to address environmentally relevant properties of chemicals.

Hyper-polyhedron model applied to molecular screening of guanidines as Na/H exchange inhibitors.

PubMed

Bao, Xin-Hua; Lu, Wen-Cong; Liu, Liang; Chen, Nian-Yi

2003-05-01

To investigate structure-activity relationships of N-(3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl) guanidines in Na/H exchange inhibitory activities and probe into a new method of the computer-aided molecular screening. The hyper-polyhedron model (HPM) was proposed in our lab. The samples with probably higher activities could be determined in such a way that their representing points should be in the hyper-polyhedron region where all known samples with high activities were distributed. And the predictive ability of different methods available was tested by the cross-validation experiment. The accurate rate of molecular screening of N-(3-Oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl) guanidines by HPM was much higher than that obtained by PCA (principal component analysis) and Fisher methods for the data set available here. Therefore, HPM could be used as a powerful tool for screening new compounds with probably higher activities.

Structural Analysis Of CD59 Of Chinese Tree Shrew: A New Reference Molecule For Human Immune System Specific CD59 Drug Discovery.

PubMed

Panda, Subhamay; Kumari, Leena; Panda, Santamay

2017-11-17

Chinese tree shrews (Tupaia belangeri chinensis) bear several characteristics that are considered to be very crucial for utilizing in animal experimental models in biomedical research. Subsequent to the identification of key aspects and signaling pathways in nervous and immune systems, it is revealed that tree shrews acquires shared common as well as unique characteristics, and hence offers a genetic basis for employing this animal as a prospective model for biomedical research. CD59 glycoprotein, commonly referred to as MAC-inhibitory protein (MAC-IP), membrane inhibitor of reactive lysis (MIRL), or protectin, is encoded by the CD59 gene in human beings. It is the member of the LY6/uPAR/alpha-neurotoxin protein family. With this initial point the objective of this study was to determine a comparative composite based structure of CD59 of Chinese tree shrew. The additional objective of this study was to examine the distribution of negatively and positively charged amino acid over molecular modeled structure, distribution of secondary structural elements, hydrophobicity molecular surface analysis and electrostatic potential analysis with the assistance of several bioinformatical analytical tools. CD59 Amino acid sequence of Chinese tree shrew collected from the online database system of National Centre for Biotechnology Information. SignalP 4.0 online server was employed for detection of signal peptide instance within the protein sequence of CD59. Molecular model structure of CD59 protein was generated by the Iterative Threading ASSEmbly Refinement (I-TASSER) suite. The confirmation for three-dimensional structural model was evaluated by structure validation tools. Location of negatively and positively charged amino acid over molecular modeled structure, distribution of secondary structural elements, and hydrophobicity molecular surface analysis was performed with the help of Chimera tool. Electrostatic potential analysis was carried out with the adaptive Poisson-Boltzmann solver package. Subsequently validated model was used for the functionally critical amino acids and active site prediction. The functionally critical amino acids and ligand- binding site (LBS) of the proteins (modeled) was determined using the COACH program. Analysis of Ramachandran plot for Chinese tree shrew depicted that overall, 100% of the residues in homology model were observed in allowed and favored regions, sequentially leading to the validation of the standard of generated protein structural model. In case of CD59 of Chinese tree shrew, the total score of G-factor was found to be -0.66 that was generally larger than the acceptable value. This approach suggests the significance and acceptability of the modeled structure of CD59 of Chinese tree shrew. The molecular model data in cooperation to other relevant post model analysis data put forward molecular insight to protecting activity of CD59 protein molecule of Chinese tree shrew. In the present study, we have proposed the first molecular model structure of uncharted CD59 of Chinese tree shrew by significantly utilizing the comparative composite modeling approach. Therefore, the development of a structural model of the CD59 protein was carried out and analyzed further for deducing molecular enrichment technique. The collaborative effort of molecular model and other relevant data of post model analysis carry forward molecular understanding to protecting activity of CD59 functions towards better insight of features of this natural lead compound. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Progress with modeling activity landscapes in drug discovery.

PubMed

Vogt, Martin

2018-04-19

Activity landscapes (ALs) are representations and models of compound data sets annotated with a target-specific activity. In contrast to quantitative structure-activity relationship (QSAR) models, ALs aim at characterizing structure-activity relationships (SARs) on a large-scale level encompassing all active compounds for specific targets. The popularity of AL modeling has grown substantially with the public availability of large activity-annotated compound data sets. AL modeling crucially depends on molecular representations and similarity metrics used to assess structural similarity. Areas covered: The concepts of AL modeling are introduced and its basis in quantitatively assessing molecular similarity is discussed. The different types of AL modeling approaches are introduced. AL designs can broadly be divided into three categories: compound-pair based, dimensionality reduction, and network approaches. Recent developments for each of these categories are discussed focusing on the application of mathematical, statistical, and machine learning tools for AL modeling. AL modeling using chemical space networks is covered in more detail. Expert opinion: AL modeling has remained a largely descriptive approach for the analysis of SARs. Beyond mere visualization, the application of analytical tools from statistics, machine learning and network theory has aided in the sophistication of AL designs and provides a step forward in transforming ALs from descriptive to predictive tools. To this end, optimizing representations that encode activity relevant features of molecules might prove to be a crucial step.

Investigation of antigen-antibody interactions of sulfonamides with a monoclonal antibody in a fluorescence polarization immunoassay using 3D-QSAR models

USDA-ARS?s Scientific Manuscript database

A three-dimensional quantitative structure-activity relationship (3D-QSAR) model of sulfonamide analogs binding a monoclonal antibody (MAbSMR) produced against sulfamerazine was carried out by Distance Comparison (DISCOtech), comparative molecular field analysis (CoMFA), and comparative molecular si...

Insights into structure and activity of natural compound inhibitors of pneumolysin

PubMed Central

Li, Hongen; Zhao, Xiaoran; Deng, Xuming; Wang, Jianfeng; Song, Meng; Niu, Xiaodi; Peng, Liping

2017-01-01

Pneumolysin is the one of the major virulence factor of the bacterium Streptococcus pneumoniae. In previous report, it is shown that β-sitosterol, a natural compound without antimicrobial activity, is a potent antagonist of pneumolysin. Here, two new pneumolysin natural compound inhibitors, with differential activity, were discovered via haemolysis assay. To explore the key factor of the conformation for the inhibition activity, the interactions between five natural compound inhibitors with differential activity and pneumolysin were reported using molecular modelling, the potential of mean force profiles. Interestingly, it is found that incorporation of the single bond (C22-C23-C24-C25) to replace the double bond (hydrocarbon sidechain) improved the anti-haemolytic activity. In view of the molecular modelling, binding of the five inhibitors to the conserved loop region (Val372, Leu460, and Tyr461) of the cholesterol binding sites led to stable complex systems, which was consistent with the result of β-sitosterol. Owing to the single bond (C22-C23-C24-C25), campesterol and brassicasterol could form strong interactions with Val372 and show higher anti-haemolytic activity, which indicated that the single bond (C22-C23-C24-C25) in inhibitors was required for the anti-haemolytic activity. Overall, the current molecular modelling work provides a starting point for the development of rational design and higher activity pneumolysin inhibitors. PMID:28165051

Combinatorially-generated library of 6-fluoroquinolone analogs as potential novel antitubercular agents: a chemometric and molecular modeling assessment.

PubMed

Minovski, Nikola; Perdih, Andrej; Solmajer, Tom

2012-05-01

The virtual combinatorial chemistry approach as a methodology for generating chemical libraries of structurally-similar analogs in a virtual environment was employed for building a general mixed virtual combinatorial library with a total of 53.871 6-FQ structural analogs, introducing the real synthetic pathways of three well known 6-FQ inhibitors. The druggability properties of the generated combinatorial 6-FQs were assessed using an in-house developed drug-likeness filter integrating the Lipinski/Veber rule-sets. The compounds recognized as drug-like were used as an external set for prediction of the biological activity values using a neural-networks (NN) model based on an experimentally-determined set of active 6-FQs. Furthermore, a subset of compounds was extracted from the pool of drug-like 6-FQs, with predicted biological activity, and subsequently used in virtual screening (VS) campaign combining pharmacophore modeling and molecular docking studies. This complex scheme, a powerful combination of chemometric and molecular modeling approaches provided novel QSAR guidelines that could aid in the further lead development of 6-FQs agents.

Design, synthesis, biological evaluation, and molecular modeling studies of chalcone-rivastigmine hybrids as cholinesterase inhibitors.

PubMed

Wang, Ling; Wang, Yu; Tian, Yiguang; Shang, Jinling; Sun, Xiaoou; Chen, Hongzhuan; Wang, Hao; Tan, Wen

2017-01-01

A series of novel chalcone-rivastigmine hybrids were designed, synthesized, and tested in vitro for their ability to inhibit human acetylcholinesterase and butyrylcholinesterase. Most of the target compounds showed hBChE selective activity in the micro- and submicromolar ranges. The most potent compound 3 exhibited comparable IC 50 to the commercially available drug (rivastigmine). To better understand their structure activity relationships (SAR) and mechanisms of enzyme-inhibitor interactions, kinetic and molecular modeling studies including molecular docking and molecular dynamics (MD) simulations were carried out. Furthermore, compound 3 blocks the formation of reactive oxygen species (ROS) in SH-SY5Y cells and shows the required druggability and low cytotoxicity, suggesting this hybrid is a promising multifunctional drug candidate for Alzheimer's disease (AD) treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

Modelling the interactions between animal venom peptides and membrane proteins.

PubMed

Hung, Andrew; Kuyucak, Serdar; Schroeder, Christina I; Kaas, Quentin

2017-12-01

The active components of animal venoms are mostly peptide toxins, which typically target ion channels and receptors of both the central and peripheral nervous system, interfering with action potential conduction and/or synaptic transmission. The high degree of sequence conservation of their molecular targets makes a range of these toxins active at human receptors. The high selectivity and potency displayed by some of these toxins have prompted their use as pharmacological tools as well as drugs or drug leads. Molecular modelling has played an essential role in increasing our molecular-level understanding of the activity and specificity of animal toxins, as well as engineering them for biotechnological and pharmaceutical applications. This review focuses on the biological insights gained from computational and experimental studies of animal venom toxins interacting with membranes and ion channels. A host of recent X-ray crystallography and electron-microscopy structures of the toxin targets has contributed to a dramatic increase in the accuracy of the molecular models of toxin binding modes greatly advancing this exciting field of study. This article is part of the Special Issue entitled 'Venom-derived Peptides as Pharmacological Tools.' Copyright © 2017 Elsevier Ltd. All rights reserved.

An Evaluation of Explicit Receptor Flexibility in Molecular Docking Using Molecular Dynamics and Torsion Angle Molecular Dynamics.

PubMed

Armen, Roger S; Chen, Jianhan; Brooks, Charles L

2009-10-13

Incorporating receptor flexibility into molecular docking should improve results for flexible proteins. However, the incorporation of explicit all-atom flexibility with molecular dynamics for the entire protein chain may also introduce significant error and "noise" that could decrease docking accuracy and deteriorate the ability of a scoring function to rank native-like poses. We address this apparent paradox by comparing the success of several flexible receptor models in cross-docking and multiple receptor ensemble docking for p38α mitogen-activated protein (MAP) kinase. Explicit all-atom receptor flexibility has been incorporated into a CHARMM-based molecular docking method (CDOCKER) using both molecular dynamics (MD) and torsion angle molecular dynamics (TAMD) for the refinement of predicted protein-ligand binding geometries. These flexible receptor models have been evaluated, and the accuracy and efficiency of TAMD sampling is directly compared to MD sampling. Several flexible receptor models are compared, encompassing flexible side chains, flexible loops, multiple flexible backbone segments, and treatment of the entire chain as flexible. We find that although including side chain and some backbone flexibility is required for improved docking accuracy as expected, docking accuracy also diminishes as additional and unnecessary receptor flexibility is included into the conformational search space. Ensemble docking results demonstrate that including protein flexibility leads to to improved agreement with binding data for 227 active compounds. This comparison also demonstrates that a flexible receptor model enriches high affinity compound identification without significantly increasing the number of false positives from low affinity compounds.

An Evaluation of Explicit Receptor Flexibility in Molecular Docking Using Molecular Dynamics and Torsion Angle Molecular Dynamics

PubMed Central

Armen, Roger S.; Chen, Jianhan; Brooks, Charles L.

2009-01-01

Incorporating receptor flexibility into molecular docking should improve results for flexible proteins. However, the incorporation of explicit all-atom flexibility with molecular dynamics for the entire protein chain may also introduce significant error and “noise” that could decrease docking accuracy and deteriorate the ability of a scoring function to rank native-like poses. We address this apparent paradox by comparing the success of several flexible receptor models in cross-docking and multiple receptor ensemble docking for p38α mitogen-activated protein (MAP) kinase. Explicit all-atom receptor flexibility has been incorporated into a CHARMM-based molecular docking method (CDOCKER) using both molecular dynamics (MD) and torsion angle molecular dynamics (TAMD) for the refinement of predicted protein-ligand binding geometries. These flexible receptor models have been evaluated, and the accuracy and efficiency of TAMD sampling is directly compared to MD sampling. Several flexible receptor models are compared, encompassing flexible side chains, flexible loops, multiple flexible backbone segments, and treatment of the entire chain as flexible. We find that although including side chain and some backbone flexibility is required for improved docking accuracy as expected, docking accuracy also diminishes as additional and unnecessary receptor flexibility is included into the conformational search space. Ensemble docking results demonstrate that including protein flexibility leads to to improved agreement with binding data for 227 active compounds. This comparison also demonstrates that a flexible receptor model enriches high affinity compound identification without significantly increasing the number of false positives from low affinity compounds. PMID:20160879

Investigating the binding mechanism of novel 6-aminonicotinate-based antagonists with P2Y12 by 3D-QSAR, docking and molecular dynamics simulations.

PubMed

Zhou, Shengfu; Fang, Danqing; Tan, Shepei; Lin, Weicong; Wu, Wenjuan; Zheng, Kangcheng

2017-10-01

P2Y 12 receptor is an attractive target for the anti-platelet therapies, treating various thrombotic diseases. In this work, a total of 107 6-aminonicotinate-based compounds as potent P2Y 12 antagonists were studies by a molecular modeling study combining three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulations to explore the decisive binding conformations of these antagonists with P2Y 12 and the structural features for the activity. The optimum CoMFA and CoMSIA models identified satisfactory robustness and good predictive ability, with R 2  = .983, q 2  = .805, [Formula: see text] = .881 for CoMFA model, and R 2  = .935, q 2  = .762, [Formula: see text] = .690 for CoMSIA model, respectively. The probable binding modes of compounds and key amino acid residues were revealed by molecular docking. MD simulations and MM/GBSA free energy calculations were further performed to validate the rationality of docking results and to compare the binding modes of several compound pairs with different activities, and the key residues (Val102, Tyr105, Tyr109, His187, Val190, Asn191, Phe252, His253, Arg256, Tyr259, Thr260, Val279, and Lys280) for the higher activity were pointed out. The binding energy decomposition indicated that the hydrophobic and hydrogen bond interactions play important roles for the binding of compounds to P2Y 12 . We hope these results could be helpful in design of potent and selective P2Y 12 antagonists.

Asymmetric bagging and feature selection for activities prediction of drug molecules.

PubMed

Li, Guo-Zheng; Meng, Hao-Hua; Lu, Wen-Cong; Yang, Jack Y; Yang, Mary Qu

2008-05-28

Activities of drug molecules can be predicted by QSAR (quantitative structure activity relationship) models, which overcomes the disadvantages of high cost and long cycle by employing the traditional experimental method. With the fact that the number of drug molecules with positive activity is rather fewer than that of negatives, it is important to predict molecular activities considering such an unbalanced situation. Here, asymmetric bagging and feature selection are introduced into the problem and asymmetric bagging of support vector machines (asBagging) is proposed on predicting drug activities to treat the unbalanced problem. At the same time, the features extracted from the structures of drug molecules affect prediction accuracy of QSAR models. Therefore, a novel algorithm named PRIFEAB is proposed, which applies an embedded feature selection method to remove redundant and irrelevant features for asBagging. Numerical experimental results on a data set of molecular activities show that asBagging improve the AUC and sensitivity values of molecular activities and PRIFEAB with feature selection further helps to improve the prediction ability. Asymmetric bagging can help to improve prediction accuracy of activities of drug molecules, which can be furthermore improved by performing feature selection to select relevant features from the drug molecules data sets.

Mechanochemical pattern formation in simple models of active viscoelastic fluids and solids

NASA Astrophysics Data System (ADS)

Alonso, Sergio; Radszuweit, Markus; Engel, Harald; Bär, Markus

2017-11-01

The cytoskeleton of the organism Physarum polycephalum is a prominent example of a complex active viscoelastic material wherein stresses induce flows along the organism as a result of the action of molecular motors and their regulation by calcium ions. Experiments in Physarum polycephalum have revealed a rich variety of mechanochemical patterns including standing, traveling and rotating waves that arise from instabilities of spatially homogeneous states without gradients in stresses and resulting flows. Herein, we investigate simple models where an active stress induced by molecular motors is coupled to a model describing the passive viscoelastic properties of the cellular material. Specifically, two models for viscoelastic fluids (Maxwell and Jeffrey model) and two models for viscoelastic solids (Kelvin-Voigt and Standard model) are investigated. Our focus is on the analysis of the conditions that cause destabilization of spatially homogeneous states and the related onset of mechano-chemical waves and patterns. We carry out linear stability analyses and numerical simulations in one spatial dimension for different models. In general, sufficiently strong activity leads to waves and patterns. The primary instability is stationary for all active fluids considered, whereas all active solids have an oscillatory primary instability. All instabilities found are of long-wavelength nature reflecting the conservation of the total calcium concentration in the models studied.

Hierarchical Modeling of Activation Mechanisms in the ABL and EGFR Kinase Domains: Thermodynamic and Mechanistic Catalysts of Kinase Activation by Cancer Mutations

PubMed Central

Dixit, Anshuman; Verkhivker, Gennady M.

2009-01-01

Structural and functional studies of the ABL and EGFR kinase domains have recently suggested a common mechanism of activation by cancer-causing mutations. However, dynamics and mechanistic aspects of kinase activation by cancer mutations that stimulate conformational transitions and thermodynamic stabilization of the constitutively active kinase form remain elusive. We present a large-scale computational investigation of activation mechanisms in the ABL and EGFR kinase domains by a panel of clinically important cancer mutants ABL-T315I, ABL-L387M, EGFR-T790M, and EGFR-L858R. We have also simulated the activating effect of the gatekeeper mutation on conformational dynamics and allosteric interactions in functional states of the ABL-SH2-SH3 regulatory complexes. A comprehensive analysis was conducted using a hierarchy of computational approaches that included homology modeling, molecular dynamics simulations, protein stability analysis, targeted molecular dynamics, and molecular docking. Collectively, the results of this study have revealed thermodynamic and mechanistic catalysts of kinase activation by major cancer-causing mutations in the ABL and EGFR kinase domains. By using multiple crystallographic states of ABL and EGFR, computer simulations have allowed one to map dynamics of conformational fluctuations and transitions in the normal (wild-type) and oncogenic kinase forms. A proposed multi-stage mechanistic model of activation involves a series of cooperative transitions between different conformational states, including assembly of the hydrophobic spine, the formation of the Src-like intermediate structure, and a cooperative breakage and formation of characteristic salt bridges, which signify transition to the active kinase form. We suggest that molecular mechanisms of activation by cancer mutations could mimic the activation process of the normal kinase, yet exploiting conserved structural catalysts to accelerate a conformational transition and the enhanced stabilization of the active kinase form. The results of this study reconcile current experimental data with insights from theoretical approaches, pointing to general mechanistic aspects of activating transitions in protein kinases. PMID:19714203

Structure- and ligand-based structure-activity relationships for a series of inhibitors of aldolase.

PubMed

Ferreira, Leonardo G; Andricopulo, Adriano D

2012-12-01

Aldolase has emerged as a promising molecular target for the treatment of human African trypanosomiasis. Over the last years, due to the increasing number of patients infected with Trypanosoma brucei, there is an urgent need for new drugs to treat this neglected disease. In the present study, two-dimensional fragment-based quantitative-structure activity relationship (QSAR) models were generated for a series of inhibitors of aldolase. Through the application of leave-one-out and leave-many-out cross-validation procedures, significant correlation coefficients were obtained (r²=0.98 and q²=0.77) as an indication of the statistical internal and external consistency of the models. The best model was employed to predict pKi values for a series of test set compounds, and the predicted values were in good agreement with the experimental results, showing the power of the model for untested compounds. Moreover, structure-based molecular modeling studies were performed to investigate the binding mode of the inhibitors in the active site of the parasitic target enzyme. The structural and QSAR results provided useful molecular information for the design of new aldolase inhibitors within this structural class.

Homology modeling and molecular dynamics simulation of N-myristoyltransferase from protozoan parasites: active site characterization and insights into rational inhibitor design

NASA Astrophysics Data System (ADS)

Sheng, Chunquan; Ji, Haitao; Miao, Zhenyuan; Che, Xiaoyin; Yao, Jianzhong; Wang, Wenya; Dong, Guoqiang; Guo, Wei; Lü, Jiaguo; Zhang, Wannian

2009-06-01

Myristoyl-CoA:protein N-myristoyltransferase (NMT) is a cytosolic monomeric enzyme that catalyzes the transfer of the myristoyl group from myristoyl-CoA to the N-terminal glycine of a number of eukaryotic cellular and viral proteins. Recent experimental data suggest NMT from parasites could be a promising new target for the design of novel antiparasitic agents with new mode of action. However, the active site topology and inhibitor specificity of these enzymes remain unclear. In this study, three-dimensional models of NMT from Plasmodium falciparum (PfNMT), Leishmania major (LmNMT) and Trypanosoma brucei (TbNMT) were constructed on the basis of the crystal structures of fungal NMTs using homology modeling method. The models were further refined by energy minimization and molecular dynamics simulations. The active sites of PfNMT, LmNMT and TbNMT were characterized by multiple copy simultaneous search (MCSS). MCSS functional maps reveal that PfNMT, LmNMT and TbNMT share a similar active site topology, which is defined by two hydrophobic pockets, a hydrogen-bonding (HB) pocket, a negatively-charged HB pocket and a positively-charged HB pocket. Flexible docking approaches were then employed to dock known inhibitors into the active site of PfNMT. The binding mode, structure-activity relationships and selectivity of inhibitors were investigated in detail. From the results of molecular modeling, the active site architecture and certain key residues responsible for inhibitor binding were identified, which provided insights for the design of novel inhibitors of parasitic NMTs.

Computer-assisted determination of minimum energy conformations. 7: A pharmacophore model of the active region of the alpha2-adrenoceptor

NASA Astrophysics Data System (ADS)

Ashman, William P.; Mickiewicz, A. P.; Nelson, Todd M.

1992-09-01

Molecular modeling and computational chemistry techniques are used to analyze compounds in developing pharmacophores of biological receptors to use as templates in structure activity relationship studies and to design new chemicals having physiological activity of interest. In this study, the results of x-ray crystal analyses and PM3 semi-empirical molecular orbital conformational analyses are used to determine the three-dimensional representations of selected adrenergic compounds known to be agonists with the alpha2-adrenoceptor in achieving optimized geometries and electrostatic parameters. The alpha2-adrenergic agonists interact with the adrenergic system receptors to produce various increases or decreases in hemodynamic responses (i.e., hypertension, hypotension, and bradycardia) and sedation. A pharmacophore model of the active region of the alpha2-adrenoceptor is described based on the superimposition of common structural, electrostatic, and physicochemical features of the compounds. Using the model to predict compound adrenergic activity and to design alpha2-adrenergic compounds is discussed.

The molecular basis of the effect of temperature on enzyme activity.

PubMed

Daniel, Roy M; Peterson, Michelle E; Danson, Michael J; Price, Nicholas C; Kelly, Sharon M; Monk, Colin R; Weinberg, Cristina S; Oudshoorn, Matthew L; Lee, Charles K

2009-12-23

Experimental data show that the effect of temperature on enzymes cannot be adequately explained in terms of a two-state model based on increases in activity and denaturation. The Equilibrium Model provides a quantitative explanation of enzyme thermal behaviour under reaction conditions by introducing an inactive (but not denatured) intermediate in rapid equilibrium with the active form. The temperature midpoint (Teq) of the rapid equilibration between the two forms is related to the growth temperature of the organism, and the enthalpy of the equilibrium (DeltaHeq) to its ability to function over various temperature ranges. In the present study, we show that the difference between the active and inactive forms is at the enzyme active site. The results reveal an apparently universal mechanism, independent of enzyme reaction or structure, based at or near the active site, by which enzymes lose activity as temperature rises, as opposed to denaturation which is global. Results show that activity losses below Teq may lead to significant errors in the determination of DeltaG*cat made on the basis of the two-state ('Classical') model, and the measured kcat will then not be a true indication of an enzyme's catalytic power. Overall, the results provide a molecular rationale for observations that the active site tends to be more flexible than the enzyme as a whole, and that activity losses precede denaturation, and provide a general explanation in molecular terms for the effect of temperature on enzyme activity.

3D-QSAR (CoMFA, CoMSIA), molecular docking and molecular dynamics simulations study of 6-aryl-5-cyano-pyrimidine derivatives to explore the structure requirements of LSD1 inhibitors.

PubMed

Ding, Lina; Wang, Zhi-Zheng; Sun, Xu-Dong; Yang, Jing; Ma, Chao-Ya; Li, Wen; Liu, Hong-Min

2017-08-01

Recently, Histone Lysine Specific Demethylase 1 (LSD1) was regarded as a promising anticancer target for the novel drug discovery. And several small molecules as LSD1 inhibitors in different structures have been reported. In this work, we carried out a molecular modeling study on the 6-aryl-5-cyano-pyrimidine fragment LSD1 inhibitors using three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics simulations. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used to generate 3D-QSAR models. The results show that the best CoMFA model has q 2 =0.802, r 2 ncv =0.979, and the best CoMSIA model has q 2 =0.799, r 2 ncv =0.982. The electrostatic, hydrophobic and H-bond donor fields play important roles in the models. Molecular docking studies predict the binding mode and the interactions between the ligand and the receptor protein. Molecular dynamics simulations results reveal that the complex of the ligand and the receptor protein are stable at 300K. All the results can provide us more useful information for our further drug design. Copyright © 2017. Published by Elsevier Ltd.

ECUT: Energy Conversion and Utilization Technologies program - Biocatalysis research activity

NASA Technical Reports Server (NTRS)

Wilcox, R.

1984-01-01

The activities of the Biocatalysis Research Activity are organized into the Biocatalysis and Molecular Modeling work elements and a supporting planning and analysis function. In the Biocatalysis work element, progress is made in developing a method for stabilizing genetically engineered traits in microorganisms, refining a technique for monitoring cells that are genetically engineered, and identifying strains of fungi for highly efficient preprocessing of biomass for optimizing the efficiency of bioreactors. In the Molecular Modeling work element, a preliminary model of the behavior of enzymes is developed. A preliminary investigation of the potential for synthesizing enzymes for use in electrochemical processes is completed. Contact with industry and universities is made to define key biocatalysis technical issues and to broaden the range of potential participants in the activity. Analyses are conducted to identify and evaluate potential concepts for future research funding.

Molecular Modeling of Heme Proteins Using MOE: Bio-Inorganic and Structure-Function Activity for Undergraduates

ERIC Educational Resources Information Center

Ray, Gigi B.; Cook, J. Whitney

2005-01-01

A biochemical molecular modeling project on heme proteins suitable for an introductory Biochemistry I class has been designed with a 2-fold objective: i) to reinforce the correlation between protein three-dimensional structure and function through a discovery oriented project, and ii) to introduce students to the fields of bioinorganic and…

PSPP: A Protein Structure Prediction Pipeline for Computing Clusters

DTIC Science & Technology

2009-07-01

Evanseck JD, et al. (1998) All-atom empirical potential for molecular modeling and dynamics studies of proteins. Journal of Physical Chemistry B 102...dimensional (3-D) protein structures are critical for the understanding of molecular mechanisms of living systems. Traditionally, X-ray crystallography...disordered proteins are often responsible for molecular recognition, molecular assembly, protein modifica- tion, and entropic chain activities in organisms [26

Potential human cholesterol esterase inhibitor design: benefits from the molecular dynamics simulations and pharmacophore modeling studies.

PubMed

John, Shalini; Thangapandian, Sundarapandian; Lee, Keun Woo

2012-01-01

Human pancreatic cholesterol esterase (hCEase) is one of the lipases found to involve in the digestion of large and broad spectrum of substrates including triglycerides, phospholipids, cholesteryl esters, etc. The presence of bile salts is found to be very important for the activation of hCEase. Molecular dynamic simulations were performed for the apoform and bile salt complexed form of hCEase using the co-ordinates of two bile salts from bovine CEase. The stability of the systems throughout the simulation time was checked and two representative structures from the highly populated regions were selected using cluster analysis. These two representative structures were used in pharmacophore model generation. The generated pharmacophore models were validated and used in database screening. The screened hits were refined for their drug-like properties based on Lipinski's rule of five and ADMET properties. The drug-like compounds were further refined by molecular docking simulation using GOLD program based on the GOLD fitness score, mode of binding, and molecular interactions with the active site amino acids. Finally, three hits of novel scaffolds were selected as potential leads to be used in novel and potent hCEase inhibitor design. The stability of binding modes and molecular interactions of these final hits were re-assured by molecular dynamics simulations.

Molecular Docking, Molecular Dynamics, and Structure–Activity Relationship Explorations of 14-Oxygenated N-Methylmorphinan-6-ones as Potent μ-Opioid Receptor Agonists

PubMed Central

2017-01-01

Among opioids, morphinans are of major importance as the most effective analgesic drugs acting primarily via μ-opioid receptor (μ-OR) activation. Our long-standing efforts in the field of opioid analgesics from the class of morphinans led to N-methylmorphinan-6-ones differently substituted at positions 5 and 14 as μ-OR agonists inducing potent analgesia and fewer undesirable effects. Herein we present the first thorough molecular modeling study and structure–activity relationship (SAR) explorations aided by docking and molecular dynamics (MD) simulations of 14-oxygenated N-methylmorphinan-6-ones to gain insights into their mode of binding to the μ-OR and interaction mechanisms. The structure of activated μ-OR provides an essential model for how ligand/μ-OR binding is encoded within small chemical differences in otherwise structurally similar morphinans. We reveal important molecular interactions that these μ-agonists share and distinguish them. The molecular docking outcomes indicate the crucial role of the relative orientation of the ligand in the μ-OR binding site, influencing the propensity of critical non-covalent interactions that are required to facilitate ligand/μ-OR interactions and receptor activation. The MD simulations point out minor differences in the tendency to form hydrogen bonds by the 4,5α-epoxy group, along with the tendency to affect the 3–7 lock switch. The emerged SARs reveal the subtle interplay between the substituents at positions 5 and 14 in the morphinan scaffold by enabling the identification of key structural elements that determine the distinct pharmacological profiles. This study provides a significant structural basis for understanding ligand binding and μ-OR activation by the 14-oxygenated N-methylmorphinan-6-ones, which should be useful for guiding drug design. PMID:28125215

Molecular Docking, Molecular Dynamics, and Structure-Activity Relationship Explorations of 14-Oxygenated N-Methylmorphinan-6-ones as Potent μ-Opioid Receptor Agonists.

PubMed

Noha, Stefan M; Schmidhammer, Helmut; Spetea, Mariana

2017-06-21

Among opioids, morphinans are of major importance as the most effective analgesic drugs acting primarily via μ-opioid receptor (μ-OR) activation. Our long-standing efforts in the field of opioid analgesics from the class of morphinans led to N-methylmorphinan-6-ones differently substituted at positions 5 and 14 as μ-OR agonists inducing potent analgesia and fewer undesirable effects. Herein we present the first thorough molecular modeling study and structure-activity relationship (SAR) explorations aided by docking and molecular dynamics (MD) simulations of 14-oxygenated N-methylmorphinan-6-ones to gain insights into their mode of binding to the μ-OR and interaction mechanisms. The structure of activated μ-OR provides an essential model for how ligand/μ-OR binding is encoded within small chemical differences in otherwise structurally similar morphinans. We reveal important molecular interactions that these μ-agonists share and distinguish them. The molecular docking outcomes indicate the crucial role of the relative orientation of the ligand in the μ-OR binding site, influencing the propensity of critical non-covalent interactions that are required to facilitate ligand/μ-OR interactions and receptor activation. The MD simulations point out minor differences in the tendency to form hydrogen bonds by the 4,5α-epoxy group, along with the tendency to affect the 3-7 lock switch. The emerged SARs reveal the subtle interplay between the substituents at positions 5 and 14 in the morphinan scaffold by enabling the identification of key structural elements that determine the distinct pharmacological profiles. This study provides a significant structural basis for understanding ligand binding and μ-OR activation by the 14-oxygenated N-methylmorphinan-6-ones, which should be useful for guiding drug design.

Combined molecular modelling and 3D-QSAR study for understanding the inhibition of NQO1 by heterocyclic quinone derivatives.

PubMed

López-Lira, Claudia; Alzate-Morales, Jans H; Paulino, Margot; Mella-Raipán, Jaime; Salas, Cristian O; Tapia, Ricardo A; Soto-Delgado, Jorge

2018-01-01

A combination of three-dimensional quantitative structure-activity relationship (3D-QSAR), and molecular modelling methods were used to understand the potent inhibitory NAD(P)H:quinone oxidoreductase 1 (NQO1) activity of a set of 52 heterocyclic quinones. Molecular docking results indicated that some favourable interactions of key amino acid residues at the binding site of NQO1 with these quinones would be responsible for an improvement of the NQO1 activity of these compounds. The main interactions involved are hydrogen bond of the amino group of residue Tyr128, π-stacking interactions with Phe106 and Phe178, and electrostatic interactions with flavin adenine dinucleotide (FADH) cofactor. Three models were prepared by 3D-QSAR analysis. The models derived from Model I and Model III, shown leave-one-out cross-validation correlation coefficients (q 2 LOO ) of .75 and .73 as well as conventional correlation coefficients (R 2 ) of .93 and .95, respectively. In addition, the external predictive abilities of these models were evaluated using a test set, producing the predicted correlation coefficients (r 2 pred ) of .76 and .74, respectively. The good concordance between the docking results and 3D-QSAR contour maps provides helpful information about a rational modification of new molecules based in quinone scaffold, in order to design more potent NQO1 inhibitors, which would exhibit highly potent antitumor activity. © 2017 John Wiley & Sons A/S.

Isolation and characterisation of sericin antifreeze peptides and molecular dynamics modelling of their ice-binding interaction.

PubMed

Wu, Jinhong; Rong, Yuzhi; Wang, Zhengwu; Zhou, Yanfu; Wang, Shaoyun; Zhao, Bo

2015-05-01

This study aimed to isolate and characterise a novel sericin antifreeze peptide and investigate its ice-binding molecular mechanism. The thermal hysteresis activity of ice-binding sericin peptides (I-SP) was measured and their activity reached as high as 0.94 °C. A P4 fraction, with high hypothermia protective activity and inhibition activity of ice recrystallisation, was obtained from I-SP, and a purified sericin peptide, named SM-AFP, with the sequence of TTSPTNVSTT and a molecular weight of 1009.50 Da was then isolated from the P4 fraction. Treatment of Lactobacillus delbrueckii Subsp. bulgaricus LB340 LYO with 100 μg/ml synthetic SM-AFP led to 1.4-fold increased survival (p < 0.05). Finally, an SM-AFP/ice binding model was constructed and results of molecular dynamics simulation suggested that the binding of SM-AFP with ice and prevention of ice crystal growth could be attributed to hydrogen bond formation, hydrophobic interaction and non-bond interactions. Sericin peptides could be developed into beneficial cryoprotectants and used in frozen food processing. Copyright © 2014 Elsevier Ltd. All rights reserved.

Modeling the chemistry of complex petroleum mixtures.

PubMed Central

Quann, R J

1998-01-01

Determining the complete molecular composition of petroleum and its refined products is not feasible with current analytical techniques because of the astronomical number of molecular components. Modeling the composition and behavior of such complex mixtures in refinery processes has accordingly evolved along a simplifying concept called lumping. Lumping reduces the complexity of the problem to a manageable form by grouping the entire set of molecular components into a handful of lumps. This traditional approach does not have a molecular basis and therefore excludes important aspects of process chemistry and molecular property fundamentals from the model's formulation. A new approach called structure-oriented lumping has been developed to model the composition and chemistry of complex mixtures at a molecular level. The central concept is to represent an individual molecular or a set of closely related isomers as a mathematical construct of certain specific and repeating structural groups. A complex mixture such as petroleum can then be represented as thousands of distinct molecular components, each having a mathematical identity. This enables the automated construction of large complex reaction networks with tens of thousands of specific reactions for simulating the chemistry of complex mixtures. Further, the method provides a convenient framework for incorporating molecular physical property correlations, existing group contribution methods, molecular thermodynamic properties, and the structure--activity relationships of chemical kinetics in the development of models. PMID:9860903

Combined 3D-QSAR modeling and molecular docking study on azacycles CCR5 antagonists

NASA Astrophysics Data System (ADS)

Ji, Yongjun; Shu, Mao; Lin, Yong; Wang, Yuanqiang; Wang, Rui; Hu, Yong; Lin, Zhihua

2013-08-01

The beta chemokine receptor 5 (CCR5) is an attractive target for pharmaceutical industry in the HIV-1, inflammation and cancer therapeutic areas. In this study, we have developed quantitative structure activity relationship (QSAR) models for a series of 41 azacycles CCR5 antagonists using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and Topomer CoMFA methods. The cross-validated coefficient q2 values of 3D-QASR (CoMFA, CoMSIA, and Topomer CoMFA) methods were 0.630, 0.758, and 0.852, respectively, the non-cross-validated R2 values were 0.979, 0.978, and 0.990, respectively. Docking studies were also employed to determine the most probable binding mode. 3D contour maps and docking results suggested that bulky groups and electron-withdrawing groups on the core part would decrease antiviral activity. Furthermore, docking results indicated that H-bonds and π bonds were favorable for antiviral activities. Finally, a set of novel derivatives with predicted activities were designed.

Regulation of circadian blood pressure: from mice to astronauts.

PubMed

Agarwal, Rajiv

2010-01-01

Circadian variation is commonly seen in healthy people; aberration in these biological rhythms is an early sign of disease. Impaired circadian variation of blood pressure (BP) has been shown to be associated with greater target organ damage and with an elevated risk of cardiovascular events independent of the BP load. The purpose of this review is to examine the physiology of circadian BP variation and propose a tripartite model that explains the regulation of circadian BP. The time-keeper in mammals resides centrally in the suprachiasmatic nucleus. Apart from this central clock, molecular clocks exist in most peripheral tissues including vascular tissue and the kidney. These molecular clocks regulate sodium balance, sympathetic function and vascular tone. A physiological model is proposed that integrates our understanding of molecular clocks in mice with the circadian BP variation among humans. The master regulator in this proposed model is the sleep-activity cycle. The equivalents of peripheral clocks are endothelial and adrenergic functions. Thus, in the proposed model, the variation in circadian BP is dependent upon three major factors: physical activity, autonomic function, and sodium sensitivity. The integrated consideration of physical activity, autonomic function, and sodium sensitivity appears to explain the physiology of circadian BP variation and the pathophysiology of disrupted BP rhythms in various conditions and disease states. Our understanding of molecular clocks in mice may help to explain the provenance of blunted circadian BP variation even among astronauts.

Quantum Mechanics/Molecular Mechanics Modeling of Drug Metabolism: Mexiletine N-Hydroxylation by Cytochrome P450 1A2.

PubMed

Lonsdale, Richard; Fort, Rachel M; Rydberg, Patrik; Harvey, Jeremy N; Mulholland, Adrian J

2016-06-20

The mechanism of cytochrome P450(CYP)-catalyzed hydroxylation of primary amines is currently unclear and is relevant to drug metabolism; previous small model calculations have suggested two possible mechanisms: direct N-oxidation and H-abstraction/rebound. We have modeled the N-hydroxylation of (R)-mexiletine in CYP1A2 with hybrid quantum mechanics/molecular mechanics (QM/MM) methods, providing a more detailed and realistic model. Multiple reaction barriers have been calculated at the QM(B3LYP-D)/MM(CHARMM27) level for the direct N-oxidation and H-abstraction/rebound mechanisms. Our calculated barriers indicate that the direct N-oxidation mechanism is preferred and proceeds via the doublet spin state of Compound I. Molecular dynamics simulations indicate that the presence of an ordered water molecule in the active site assists in the binding of mexiletine in the active site, but this is not a prerequisite for reaction via either mechanism. Several active site residues play a role in the binding of mexiletine in the active site, including Thr124 and Phe226. This work reveals key details of the N-hydroxylation of mexiletine and further demonstrates that mechanistic studies using QM/MM methods are useful for understanding drug metabolism.

Synthesis, biological evaluation and molecular modeling of novel series of pyridine derivatives as anticancer, anti-inflammatory and analgesic agents

NASA Astrophysics Data System (ADS)

Helal, M. H.; El-Awdan, S. A.; Salem, M. A.; Abd-elaziz, T. A.; Moahamed, Y. A.; El-Sherif, A. A.; Mohamed, G. A. M.

2015-01-01

This paper presents a combined synthesis; characterization, computational and biological activity studies of novel series of pyridines heterocyclic compounds. The compounds have been characterized by elemental analyses and spectral like IR, 1H NMR, 13C NMR and MS studies. Michael addition of substituted-2-methoxycarbonylacetanilide 2a,b on the α-substituted cinnamonitriles 3a-d gave the corresponding 2-pyridone derivatives 5-10. Structures of the titled compounds cited in this article were elucidated by spectrometric data (IR, 1H NMR, 13C NMR and MS). The molecular modeling of the synthesized compounds has been drawn and their molecular parameters were calculated. Also, valuable information is obtained from the calculation of molecular parameters including electronegativity, net dipole moment of the compounds, total energy, electronic energy, binding energy, HOMO and LUMO energy. Various in vitro antitumor as well as in vivo anti-inflammatory and analgesic activities of the synthesized compounds were investigated. Evaluation of anti-inflammatory activity of test compounds was performed using carrageenan induced paw edema in rats. All the tested compounds showed moderate to good activity. The SAR results indicate that all compounds showed moderate to good activity, among these 7 and 10 compounds having -N(CH3)2 group are most effective.

Molecular docking and 3D-QSAR studies on triazolinone and pyridazinone, non-nucleoside inhibitor of HIV-1 reverse transcriptase.

PubMed

Sivan, Sree Kanth; Manga, Vijjulatha

2010-06-01

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are allosteric inhibitors of the HIV-1 reverse transcriptase. Recently a series of Triazolinone and Pyridazinone were reported as potent inhibitors of HIV-1 wild type reverse transcriptase. In the present study, docking and 3D quantitative structure activity relationship (3D QSAR) studies involving comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on 31 molecules. Ligands were built and minimized using Tripos force field and applying Gasteiger-Hückel charges. These ligands were docked into protein active site using GLIDE 4.0. The docked poses were analyzed; the best docked poses were selected and aligned. CoMFA and CoMSIA fields were calculated using SYBYL6.9. The molecules were divided into training set and test set, a PLS analysis was performed and QSAR models were generated. The model showed good statistical reliability which is evident from the r2 nv, q2 loo and r2 pred values. The CoMFA model provides the most significant correlation of steric and electrostatic fields with biological activities. The CoMSIA model provides a correlation of steric, electrostatic, acceptor and hydrophobic fields with biological activities. The information rendered by 3D QSAR model initiated us to optimize the lead and design new potential inhibitors.

Structural parameterization and functional prediction of antigenic polypeptome sequences with biological activity through quantitative sequence-activity models (QSAM) by molecular electronegativity edge-distance vector (VMED).

PubMed

Li, ZhiLiang; Wu, ShiRong; Chen, ZeCong; Ye, Nancy; Yang, ShengXi; Liao, ChunYang; Zhang, MengJun; Yang, Li; Mei, Hu; Yang, Yan; Zhao, Na; Zhou, Yuan; Zhou, Ping; Xiong, Qing; Xu, Hong; Liu, ShuShen; Ling, ZiHua; Chen, Gang; Li, GenRong

2007-10-01

Only from the primary structures of peptides, a new set of descriptors called the molecular electronegativity edge-distance vector (VMED) was proposed and applied to describing and characterizing the molecular structures of oligopeptides and polypeptides, based on the electronegativity of each atom or electronic charge index (ECI) of atomic clusters and the bonding distance between atom-pairs. Here, the molecular structures of antigenic polypeptides were well expressed in order to propose the automated technique for the computerized identification of helper T lymphocyte (Th) epitopes. Furthermore, a modified MED vector was proposed from the primary structures of polypeptides, based on the ECI and the relative bonding distance of the fundamental skeleton groups. The side-chains of each amino acid were here treated as a pseudo-atom. The developed VMED was easy to calculate and able to work. Some quantitative model was established for 28 immunogenic or antigenic polypeptides (AGPP) with 14 (1-14) A(d) and 14 other restricted activities assigned as "1"(+) and "0"(-), respectively. The latter comprised 6 A(b)(15-20), 3 A(k)(21-23), 2 E(k)(24-26), 2 H-2(k)(27 and 28) restricted sequences. Good results were obtained with 90% correct classification (only 2 wrong ones for 20 training samples) and 100% correct prediction (none wrong for 8 testing samples); while contrastively 100% correct classification (none wrong for 20 training samples) and 88% correct classification (1 wrong for 8 testing samples). Both stochastic samplings and cross validations were performed to demonstrate good performance. The described method may also be suitable for estimation and prediction of classes I and II for major histocompatibility antigen (MHC) epitope of human. It will be useful in immune identification and recognition of proteins and genes and in the design and development of subunit vaccines. Several quantitative structure activity relationship (QSAR) models were developed for various oligopeptides and polypeptides including 58 dipeptides and 31 pentapeptides with angiotensin converting enzyme (ACE) inhibition by multiple linear regression (MLR) method. In order to explain the ability to characterize molecular structure of polypeptides, a molecular modeling investigation on QSAR was performed for functional prediction of polypeptide sequences with antigenic activity and heptapeptide sequences with tachykinin activity through quantitative sequence-activity models (QSAMs) by the molecular electronegativity edge-distance vector (VMED). The results showed that VMED exhibited both excellent structural selectivity and good activity prediction. Moreover, the results showed that VMED behaved quite well for both QSAR and QSAM of poly-and oligopeptides, which exhibited both good estimation ability and prediction power, equal to or better than those reported in the previous references. Finally, a preliminary conclusion was drawn: both classical and modified MED vectors were very useful structural descriptors. Some suggestions were proposed for further studies on QSAR/QSAM of proteins in various fields.

Testing a structural model for viral DNA packaging motor function by optical tweezers measurements, site directed mutagenesis, and molecular dynamics calculations

NASA Astrophysics Data System (ADS)

Keller, Nicholas A.; Migliori, Amy D.; Arya, Gaurav; Rao, Venigalla B.; Smith, Douglas E.

2013-09-01

Many double-stranded DNA viruses employ a molecular motor to package DNA into preformed capsid shells. Based on structures of phage T4 motor proteins determined by X-ray crystallography and cryo-electron microscopy, Rao, Rossmann and coworkers recently proposed a structural model for motor function. They proposed that DNA is ratcheted by a large conformational change driven by electrostatic interactions between charged residues at an interface between two globular domains of the motor protein. We have conducted experiments to test this model by studying the effect on packaging under applied load of site-directed changes altering these residues. We observe significant impairment of packaging activity including reductions in packaging rate, percent time packaging, and time active under high load. We show that these measured impairments correlate well with alterations in free energies associated with the conformational change predicted by molecular dynamics simulations.

Molecular activity prediction by means of supervised subspace projection based ensembles of classifiers.

PubMed

Cerruela García, G; García-Pedrajas, N; Luque Ruiz, I; Gómez-Nieto, M Á

2018-03-01

This paper proposes a method for molecular activity prediction in QSAR studies using ensembles of classifiers constructed by means of two supervised subspace projection methods, namely nonparametric discriminant analysis (NDA) and hybrid discriminant analysis (HDA). We studied the performance of the proposed ensembles compared to classical ensemble methods using four molecular datasets and eight different models for the representation of the molecular structure. Using several measures and statistical tests for classifier comparison, we observe that our proposal improves the classification results with respect to classical ensemble methods. Therefore, we show that ensembles constructed using supervised subspace projections offer an effective way of creating classifiers in cheminformatics.

Cis and Trans Isomerization in Cyclic Alkenes: A Topic for Discovery Using the Results of Molecular Modeling

ERIC Educational Resources Information Center

Barrows, Susan E.; Eberlein, Thomas H.

2004-01-01

Activities in which students explore the fundamental reasons behind the unusual instability of the trans isomers in medium-sized cycloalkenes by using the results of molecular modeling are described. Exercises have been proposed to explore the structures of cycloheptene and cyclooctene by Hehre and others which would be helpful to disabuse…

Atomistic insight into the catalytic mechanism of glycosyltransferases by combined quantum mechanics/molecular mechanics (QM/MM) methods.

PubMed

Tvaroška, Igor

2015-02-11

Glycosyltransferases catalyze the formation of glycosidic bonds by assisting the transfer of a sugar residue from donors to specific acceptor molecules. Although structural and kinetic data have provided insight into mechanistic strategies employed by these enzymes, molecular modeling studies are essential for the understanding of glycosyltransferase catalyzed reactions at the atomistic level. For such modeling, combined quantum mechanics/molecular mechanics (QM/MM) methods have emerged as crucial. These methods allow the modeling of enzymatic reactions by using quantum mechanical methods for the calculation of the electronic structure of the active site models and treating the remaining enzyme environment by faster molecular mechanics methods. Herein, the application of QM/MM methods to glycosyltransferase catalyzed reactions is reviewed, and the insight from modeling of glycosyl transfer into the mechanisms and transition states structures of both inverting and retaining glycosyltransferases are discussed. Copyright © 2014 Elsevier Ltd. All rights reserved.

QSAR, DFT and molecular modeling studies of peptides from HIV-1 to describe their recognition properties by MHC-I.

PubMed

Andrade-Ochoa, S; García-Machorro, J; Bello, Martiniano; Rodríguez-Valdez, L M; Flores-Sandoval, C A; Correa-Basurto, J

2017-08-03

Human immunodeficiency virus type-1 (HIV-1) has infected more than 40 million people around the world. HIV-1 treatment still has several side effects, and the development of a vaccine, which is another potential option for decreasing human infections, has faced challenges. This work presents a computational study that includes a quantitative structure activity relationship(QSAR) using density functional theory(DFT) for reported peptides to identify the principal quantum mechanics descriptors related to peptide activity. In addition, the molecular recognition properties of these peptides are explored on major histocompatibility complex I (MHC-I) through docking and molecular dynamics (MD) simulations accompanied by the Molecular Mechanics Generalized Born Surface Area (MMGBSA) approach for correlating peptide activity reported elsewhere vs. theoretical peptide affinity. The results show that the carboxylic acid and hydroxyl groups are chemical moieties that have an inverse relationship with biological activity. The number of sulfides, pyrroles and imidazoles from the peptide structure are directly related to biological activity. In addition, the HOMO orbital energy values of the total absolute charge and the Ghose-Crippen molar refractivity of peptides are descriptors directly related to the activity and affinity on MHC-I. Docking and MD simulation studies accompanied by an MMGBSA analysis show that the binding free energy without considering the entropic contribution is energetically favorable for all the complexes. Furthermore, good peptide interaction with the most affinity is evaluated experimentally for three proteins. Overall, this study shows that the combination of quantum mechanics descriptors and molecular modeling studies could help describe the immunogenic properties of peptides from HIV-1.

Quantitative structure activity relationship studies of piperazinyl phenylalanine derivatives as VLA-4/VCAM-1 inhibitors.

PubMed

Bhargava, Dinesh; Karthikeyan, C; Moorthy, N S H N; Trivedi, Piyush

2009-09-01

QSAR study was carried out for a series of piperazinyl phenylalanine derivatives exhibiting VLA-4/VCAM-1 inhibitory activity to find out the structural features responsible for the biological activity. The QSAR study was carried out on V-life Molecular Design Suite software and the derived best QSAR model by partial least square (forward) regression method showed 85.67% variation in biological activity. The statistically significant model with high correlation coefficient (r2=0.85) was selected for further study and the resulted validation parameters of the model, crossed squared correlation coefficient (q2=0.76 and pred_r2=0.42) show the model has good predictive ability. The model showed that the parameters SaaNEindex, SsClcount slogP,and 4PathCount are highly correlated with VLA-4/VCAM-1 inhibitory activity of piperazinyl phenylalanine derivatives. The result of the study suggests that the chlorine atoms in the molecule and fourth order fragmentation patterns in the molecular skeleton favour VLA-4/VCAM-1 inhibition shown by the title compounds whereas lipophilicity and nitrogen bonded to aromatic bond are not conducive for VLA-4/VCAM-1 inhibitory activity.

Medicinal Chemistry and Molecular Modeling: An Integration to Teach Drug Structure-Activity Relationship and the Molecular Basis of Drug Action

ERIC Educational Resources Information Center

Carvalho, Ivone; Borges, Aurea D. L.; Bernardes, Lilian S. C.

2005-01-01

The use of computational chemistry and the protein data bank (PDB) to understand and predict the chemical and molecular basis involved in the drug-receptor interactions is discussed. A geometrical and chemical overview of the great structural similarity in the substrate and inhibitor is provided.

Design of biomimetic catalysts by molecular imprinting in synthetic polymers: the role of transition state stabilization.

PubMed

Wulff, Günter; Liu, Junqiu

2012-02-21

The impressive efficiency and selectivity of biological catalysts has engendered a long-standing effort to understand the details of enzyme action. It is widely accepted that enzymes accelerate reactions through their steric and electronic complementarity to the reactants in the rate-determining transition states. Thus, tight binding to the transition state of a reactant (rather than to the corresponding substrate) lowers the activation energy of the reaction, providing strong catalytic activity. Debates concerning the fundamentals of enzyme catalysis continue, however, and non-natural enzyme mimics offer important additional insight in this area. Molecular structures that mimic enzymes through the design of a predetermined binding site that stabilizes the transition state of a desired reaction are invaluable in this regard. Catalytic antibodies, which can be quite active when raised against stable transition state analogues of the corresponding reaction, represent particularly successful examples. Recently, synthetic chemistry has begun to match nature's ability to produce antibody-like binding sites with high affinities for the transition state. Thus, synthetic, molecularly imprinted polymers have been engineered to provide enzyme-like specificity and activity, and they now represent a powerful tool for creating highly efficient catalysts. In this Account, we review recent efforts to develop enzyme models through the concept of transition state stabilization. In particular, models for carboxypeptidase A were prepared through the molecular imprinting of synthetic polymers. On the basis of successful experiments with phosphonic esters as templates to arrange amidinium groups in the active site, the method was further improved by combining the concept of transition state stabilization with the introduction of special catalytic moieties, such as metal ions in a defined orientation in the active site. In this way, the imprinted polymers were able to provide both an electrostatic stabilization for the transition state through the amidinium group as well as a synergism of transition state recognition and metal ion catalysis. The result was an excellent catalyst for carbonate hydrolysis. These enzyme mimics represent the most active catalysts ever prepared through the molecular imprinting strategy. Their catalytic activity, catalytic efficiency, and catalytic proficiency clearly surpass those of the corresponding catalytic antibodies. The active structures in natural enzymes evolve within soluble proteins, typically by the refining of the folding of one polypeptide chain. To incorporate these characteristics into synthetic polymers, we used the concept of transition state stabilization to develop soluble, nanosized carboxypeptidase A models using a new polymerization method we term the "post-dilution polymerization method". With this methodology, we were able to prepare soluble, highly cross-linked, single-molecule nanoparticles. These particles have controlled molecular weights (39 kDa, for example) and, on average, one catalytically active site per particle. Our strategies have made it possible to obtain efficient new enzyme models and further advance the structural and functional analogy with natural enzymes. Moreover, this bioinspired design based on molecular imprinting in synthetic polymers offers further support for the concept of transition state stabilization in catalysis.

The discovery of novel histone lysine methyltransferase G9a inhibitors (part 1): molecular design based on a series of substituted 2,4-diamino-7- aminoalkoxyquinazoline by molecular-docking-guided 3D quantitative structure-activity relationship studies.

PubMed

Feng, Taotao; Wang, Hai; Zhang, Xiaojin; Sun, Haopeng; You, Qidong

2014-06-01

Protein lysine methyltransferase G9a, which catalyzes methylation of lysine 9 of histone H3 (H3K9) and lysine 373 (K373) of p53, is overexpressed in human cancers. This suggests that small molecular inhibitors of G9a might be attractive antitumor agents. Herein we report our efforts on the design of novel G9a inhibitor based on the 3D quantitative structure-activity relationship (3D-QSAR) analysis of a series of 2,4-diamino-7-aminoalkoxyquinazolineas G9a inhibitors. The 3D-QSAR model was generated from 47 compounds using docking based molecular alignment. The best predictions were obtained with CoMFA standard model (q2 =0.700, r2 = 0.952) and CoMSIA model combined with steric, electrostatic, hydrophobic, hydrogen bond donor and acceptor fields (q2 = 0.724, r2 =0.960). The structural requirements for substituted 2,4-diamino-7-aminoalkoxyquinazoline for G9a inhibitory activity can be obtained by analysing the COMSIA plots. Based on the information, six novel follow-up analogs were designed.

Molecular conformation of the full-length tumor suppressor NF2/Merlin—a small angle neutron scattering study

PubMed Central

Khajeh, Jahan Ali; Ju, Jeong Ho; Atchiba, Moussoubaou; Allaire, Marc; Stanley, Christopher; Heller, William T.; Callaway, David J.E.; Bu, Zimei

2014-01-01

Summary The tumor suppressor protein Merlin inhibits cell proliferation upon establishing cell-cell contacts. Because Merlin has high sequence similarity to the Ezrin-Radixin-Moesin (ERM) family of proteins, the structural model of ERM protein autoinhibition and cycling between closed/resting and open/active conformational states is often employed to explain Merlin function. However, recent biochemical studies suggest alternative molecular models of Merlin function. Here, we have determined the low resolution molecular structure and binding activity of Merlin and a Merlin(S518D) mutant that mimics the inactivating phosphorylation at S518 using small angle neutron scattering (SANS) and binding experiments. SANS shows that in solution both Merlin and Merlin(S518D) adopt a closed conformation, but binding experiments indicate that a significant fraction of either Merlin or Merlin(S518D) is capable of binding to the target protein NHERF1. Upon binding to the phosphatidylinositol 4,5-bisphosphate lipid, the wild-type Merlin adopts a more open conformation than in solution, but Merlin(S518D) remains in a closed conformation. This study supports a rheostat model of Merlin in NHERF1 binding, and contributes to resolve a controversy about the molecular conformation and binding activity of Merlin. PMID:24882693

Three-dimensional quantitative structure-activity relationship analysis for human pregnane X receptor for the prediction of CYP3A4 induction in human hepatocytes: structure-based comparative molecular field analysis.

PubMed

Handa, Koichi; Nakagome, Izumi; Yamaotsu, Noriyuki; Gouda, Hiroaki; Hirono, Shuichi

2015-01-01

The pregnane X receptor [PXR (NR1I2)] induces the expression of xenobiotic metabolic genes and transporter genes. In this study, we aimed to establish a computational method for quantifying the enzyme-inducing potencies of different compounds via their ability to activate PXR, for the application in drug discovery and development. To achieve this purpose, we developed a three-dimensional quantitative structure-activity relationship (3D-QSAR) model using comparative molecular field analysis (CoMFA) for predicting enzyme-inducing potencies, based on computer-ligand docking to multiple PXR protein structures sampled from the trajectory of a molecular dynamics simulation. Molecular mechanics-generalized born/surface area scores representing the ligand-protein-binding free energies were calculated for each ligand. As a result, the predicted enzyme-inducing potencies for compounds generated by the CoMFA model were in good agreement with the experimental values. Finally, we concluded that this 3D-QSAR model has the potential to predict the enzyme-inducing potencies of novel compounds with high precision and therefore has valuable applications in the early stages of the drug discovery process. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

QSAR and 3D QSAR of inhibitors of the epidermal growth factor receptor

NASA Astrophysics Data System (ADS)

Pinto-Bazurco, Mariano; Tsakovska, Ivanka; Pajeva, Ilza

This article reports quantitative structure-activity relationships (QSAR) and 3D QSAR models of 134 structurally diverse inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase. Free-Wilson analysis was used to derive the QSAR model. It identified the substituents in aniline, the polycyclic system, and the substituents at the 6- and 7-positions of the polycyclic system as the most important structural features. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used in the 3D QSAR modeling. The steric and electrostatic interactions proved the most important for the inhibitory effect. Both QSAR and 3D QSAR models led to consistent results. On the basis of the statistically significant models, new structures were proposed and their inhibitory activities were predicted.

Silanol-assisted carbinolamine formation in an amine-functionalized mesoporous silica surface: Theoretical investigation by fragmentation methods

DOE PAGES

de Lima Batista, Ana P.; Zahariev, Federico; Slowing, Igor I.; ...

2015-12-15

The aldol reaction catalyzed by an amine-substituted mesoporous silica nanoparticle (amine-MSN) surface was investigated using a large molecular cluster model (Si 392O 958C 6NH 361) combined with the surface integrated molecular orbital/molecular mechanics (SIMOMM) and fragment molecular orbital (FMO) methods. Three distinct pathways for the carbinolamine formation, the first step of the amine-catalyzed aldol reaction, are proposed and investigated in order to elucidate the role of the silanol environment on the catalytic capability of the amine-MSN material. Here the computational study reveals that the most likely mechanism involves the silanol groups actively participating in the reaction, forming and breaking covalentmore » bonds in the carbinolamine step. Furthermore, the active participation of MSN silanol groups in the reaction mechanism leads to a significant reduction in the overall energy barrier for the carbinolamine formation. In addition, a comparison between the findings using a minimal cluster model and the Si 392O 958C 6NH 361 cluster suggests that the use of larger models is important when heterogeneous catalysis problems are the target.« less

Anti-inflammatory activity and molecular mechanism of delphinidin 3-sambubioside, a Hibiscus anthocyanin.

PubMed

Sogo, Takayuki; Terahara, Norihiko; Hisanaga, Ayami; Kumamoto, Takuma; Yamashiro, Takaaki; Wu, Shusong; Sakao, Kozue; Hou, De-Xing

2015-01-01

Delphinidin 3-sambubioside (Dp3-Sam), a Hibiscus anthocyanin, was isolated from the dried calices of Hibiscus sabdariffa L, which has been used for folk beverages and herbal medicine although the molecular mechanisms are poorly defined. Based on the properties of Dp3-Sam and the information of inflammatory processes, we investigated the anti-inflammatory activity and molecular mechanisms in both cell and animal models in the present study. In the cell model, Dp3-Sam and Delphinidin (Dp) reduced the levels of inflammatory mediators including iNOS, NO, IL-6, MCP-1, and TNF-α induced by LPS. Cellular signaling analysis revealed that Dp3-Sam and Dp downregulated NF-κB pathway and MEK1/2-ERK1/2 signaling. In animal model, Dp3-Sam and Dp reduced the production of IL-6, MCP-1 and TNF-α and attenuated mouse paw edema induced by LPS. Our in vitro and in vivo data demonstrated that Hibiscus Dp3-Sam possessed potential anti-inflammatory properties. © 2015 International Union of Biochemistry and Molecular Biology.

Molecular dynamics, flexible docking, virtual screening, ADMET predictions, and molecular interaction field studies to design novel potential MAO-B inhibitors.

PubMed

Braun, Glaucia H; Jorge, Daniel M M; Ramos, Henrique P; Alves, Raquel M; da Silva, Vinicius B; Giuliatti, Silvana; Sampaio, Suley Vilela; Taft, Carlton A; Silva, Carlos H T P

2008-02-01

Monoamine oxidase is a flavoenzyme bound to the mitochondrial outer membranes of the cells, which is responsible for the oxidative deamination of neurotransmitter and dietary amines. It has two distinct isozymic forms, designated MAO-A and MAO-B, each displaying different substrate and inhibitor specificities. They are the well-known targets for antidepressant, Parkinson's disease, and neuroprotective drugs. Elucidation of the x-ray crystallographic structure of MAO-B has opened the way for the molecular modeling studies. In this work we have used molecular modeling, density functional theory with correlation, virtual screening, flexible docking, molecular dynamics, ADMET predictions, and molecular interaction field studies in order to design new molecules with potential higher selectivity and enzymatic inhibitory activity over MAO-B.

De Novo Design of Bioactive Small Molecules by Artificial Intelligence

PubMed Central

Merk, Daniel; Friedrich, Lukas; Grisoni, Francesca

2018-01-01

Abstract Generative artificial intelligence offers a fresh view on molecular design. We present the first‐time prospective application of a deep learning model for designing new druglike compounds with desired activities. For this purpose, we trained a recurrent neural network to capture the constitution of a large set of known bioactive compounds represented as SMILES strings. By transfer learning, this general model was fine‐tuned on recognizing retinoid X and peroxisome proliferator‐activated receptor agonists. We synthesized five top‐ranking compounds designed by the generative model. Four of the compounds revealed nanomolar to low‐micromolar receptor modulatory activity in cell‐based assays. Apparently, the computational model intrinsically captured relevant chemical and biological knowledge without the need for explicit rules. The results of this study advocate generative artificial intelligence for prospective de novo molecular design, and demonstrate the potential of these methods for future medicinal chemistry. PMID:29319225

Quantitative Structure-Activity Relationship of Insecticidal Activity of Benzyl Ether Diamidine Derivatives

NASA Astrophysics Data System (ADS)

Zhai, Mengting; Chen, Yan; Li, Jing; Zhou, Jun

2017-12-01

The molecular electrongativity distance vector (MEDV-13) was used to describe the molecular structure of benzyl ether diamidine derivatives in this paper, Based on MEDV-13, The three-parameter (M 3, M 15, M 47) QSAR model of insecticidal activity (pIC 50) for 60 benzyl ether diamidine derivatives was constructed by leaps-and-bounds regression (LBR) . The traditional correlation coefficient (R) and the cross-validation correlation coefficient (R CV ) were 0.975 and 0.971, respectively. The robustness of the regression model was validated by Jackknife method, the correlation coefficient R were between 0.971 and 0.983. Meanwhile, the independent variables in the model were tested to be no autocorrelation. The regression results indicate that the model has good robust and predictive capabilities. The research would provide theoretical guidance for the development of new generation of anti African trypanosomiasis drugs with efficiency and low toxicity.

Phosphorylation by PINK1 Releases the UBL Domain and Initializes the Conformational Opening of the E3 Ubiquitin Ligase Parkin

PubMed Central

Moussaud-Lamodière, Elisabeth L.; Dourado, Daniel F. A. R.; Flores, Samuel C.; Springer, Wolfdieter

2014-01-01

Loss-of-function mutations in PINK1 or PARKIN are the most common causes of autosomal recessive Parkinson's disease. Both gene products, the Ser/Thr kinase PINK1 and the E3 Ubiquitin ligase Parkin, functionally cooperate in a mitochondrial quality control pathway. Upon stress, PINK1 activates Parkin and enables its translocation to and ubiquitination of damaged mitochondria to facilitate their clearance from the cell. Though PINK1-dependent phosphorylation of Ser65 is an important initial step, the molecular mechanisms underlying the activation of Parkin's enzymatic functions remain unclear. Using molecular modeling, we generated a complete structural model of human Parkin at all atom resolution. At steady state, the Ub ligase is maintained inactive in a closed, auto-inhibited conformation that results from intra-molecular interactions. Evidently, Parkin has to undergo major structural rearrangements in order to unleash its catalytic activity. As a spark, we have modeled PINK1-dependent Ser65 phosphorylation in silico and provide the first molecular dynamics simulation of Parkin conformations along a sequential unfolding pathway that could release its intertwined domains and enable its catalytic activity. We combined free (unbiased) molecular dynamics simulation, Monte Carlo algorithms, and minimal-biasing methods with cell-based high content imaging and biochemical assays. Phosphorylation of Ser65 results in widening of a newly defined cleft and dissociation of the regulatory N-terminal UBL domain. This motion propagates through further opening conformations that allow binding of an Ub-loaded E2 co-enzyme. Subsequent spatial reorientation of the catalytic centers of both enzymes might facilitate the transfer of the Ub moiety to charge Parkin. Our structure-function study provides the basis to elucidate regulatory mechanisms and activity of the neuroprotective Parkin. This may open up new avenues for the development of small molecule Parkin activators through targeted drug design. PMID:25375667

Multi-Scale Computational Enzymology: Enhancing Our Understanding of Enzymatic Catalysis

PubMed Central

Gherib, Rami; Dokainish, Hisham M.; Gauld, James W.

2014-01-01

Elucidating the origin of enzymatic catalysis stands as one the great challenges of contemporary biochemistry and biophysics. The recent emergence of computational enzymology has enhanced our atomistic-level description of biocatalysis as well the kinetic and thermodynamic properties of their mechanisms. There exists a diversity of computational methods allowing the investigation of specific enzymatic properties. Small or large density functional theory models allow the comparison of a plethora of mechanistic reactive species and divergent catalytic pathways. Molecular docking can model different substrate conformations embedded within enzyme active sites and determine those with optimal binding affinities. Molecular dynamics simulations provide insights into the dynamics and roles of active site components as well as the interactions between substrate and enzymes. Hybrid quantum mechanical/molecular mechanical (QM/MM) can model reactions in active sites while considering steric and electrostatic contributions provided by the surrounding environment. Using previous studies done within our group, on OvoA, EgtB, ThrRS, LuxS and MsrA enzymatic systems, we will review how these methods can be used either independently or cooperatively to get insights into enzymatic catalysis. PMID:24384841

3D Pharmacophore-Based Virtual Screening and Docking Approaches toward the Discovery of Novel HPPD Inhibitors.

PubMed

Fu, Ying; Sun, Yi-Na; Yi, Ke-Han; Li, Ming-Qiang; Cao, Hai-Feng; Li, Jia-Zhong; Ye, Fei

2017-06-09

p -Hydroxyphenylpyruvate dioxygenase (HPPD) is not only the useful molecular target in treating life-threatening tyrosinemia type I, but also an important target for chemical herbicides. A combined in silico structure-based pharmacophore and molecular docking-based virtual screening were performed to identify novel potential HPPD inhibitors. The complex-based pharmacophore model (CBP) with 0.721 of ROC used for screening compounds showed remarkable ability to retrieve known active ligands from among decoy molecules. The ChemDiv database was screened using CBP-Hypo2 as a 3D query, and the best-fit hits subjected to molecular docking with two methods of LibDock and CDOCKER in Accelrys Discovery Studio 2.5 (DS 2.5) to discern interactions with key residues at the active site of HPPD. Four compounds with top rankings in the HipHop model and well-known binding model were finally chosen as lead compounds with potential inhibitory effects on the active site of target. The results provided powerful insight into the development of novel HPPD inhibitors herbicides using computational techniques.

Active cell-matrix coupling regulates cellular force landscapes of cohesive epithelial monolayers

NASA Astrophysics Data System (ADS)

Zhao, Tiankai; Zhang, Yao; Wei, Qiong; Shi, Xuechen; Zhao, Peng; Chen, Long-Qing; Zhang, Sulin

2018-03-01

Epithelial cells can assemble into cohesive monolayers with rich morphologies on substrates due to competition between elastic, edge, and interfacial effects. Here we present a molecularly based thermodynamic model, integrating monolayer and substrate elasticity, and force-mediated focal adhesion formation, to elucidate the active biochemical regulation over the cellular force landscapes in cohesive epithelial monolayers, corroborated by microscopy and immunofluorescence studies. The predicted extracellular traction and intercellular tension are both monolayer size and substrate stiffness dependent, suggestive of cross-talks between intercellular and extracellular activities. Our model sets a firm ground toward a versatile computational framework to uncover the molecular origins of morphogenesis and disease in multicellular epithelia.

How molecular motors work in the crowded environment of living cells: coexistence and efficiency of normal and anomalous transport.

PubMed

Goychuk, Igor; Kharchenko, Vasyl O; Metzler, Ralf

2014-01-01

Recent experiments reveal both passive subdiffusion of various nanoparticles and anomalous active transport of such particles by molecular motors in the molecularly crowded environment of living biological cells. Passive and active microrheology reveals that the origin of this anomalous dynamics is due to the viscoelasticity of the intracellular fluid. How do molecular motors perform in such a highly viscous, dissipative environment? Can we explain the observed co-existence of the anomalous transport of relatively large particles of 100 to 500 nm in size by kinesin motors with the normal transport of smaller particles by the same molecular motors? What is the efficiency of molecular motors in the anomalous transport regime? Here we answer these seemingly conflicting questions and consistently explain experimental findings in a generalization of the well-known continuous diffusion model for molecular motors with two conformational states in which viscoelastic effects are included.

How Molecular Motors Work in the Crowded Environment of Living Cells: Coexistence and Efficiency of Normal and Anomalous Transport

PubMed Central

Goychuk, Igor; Kharchenko, Vasyl O.; Metzler, Ralf

2014-01-01

Recent experiments reveal both passive subdiffusion of various nanoparticles and anomalous active transport of such particles by molecular motors in the molecularly crowded environment of living biological cells. Passive and active microrheology reveals that the origin of this anomalous dynamics is due to the viscoelasticity of the intracellular fluid. How do molecular motors perform in such a highly viscous, dissipative environment? Can we explain the observed co-existence of the anomalous transport of relatively large particles of 100 to 500 nm in size by kinesin motors with the normal transport of smaller particles by the same molecular motors? What is the efficiency of molecular motors in the anomalous transport regime? Here we answer these seemingly conflicting questions and consistently explain experimental findings in a generalization of the well-known continuous diffusion model for molecular motors with two conformational states in which viscoelastic effects are included. PMID:24626511

Transition from direct to inverted charge transport Marcus regions in molecular junctions via molecular orbital gating

NASA Astrophysics Data System (ADS)

Yuan, Li; Wang, Lejia; Garrigues, Alvar R.; Jiang, Li; Annadata, Harshini Venkata; Anguera Antonana, Marta; Barco, Enrique; Nijhuis, Christian A.

2018-04-01

Solid-state molecular tunnel junctions are often assumed to operate in the Landauer regime, which describes essentially activationless coherent tunnelling processes. In solution, on the other hand, charge transfer is described by Marcus theory, which accounts for thermally activated processes. In practice, however, thermally activated transport phenomena are frequently observed also in solid-state molecular junctions but remain poorly understood. Here, we show experimentally the transition from the Marcus to the inverted Marcus region in a solid-state molecular tunnel junction by means of intra-molecular orbital gating that can be tuned via the chemical structure of the molecule and applied bias. In the inverted Marcus region, charge transport is incoherent, yet virtually independent of temperature. Our experimental results fit well to a theoretical model that combines Landauer and Marcus theories and may have implications for the interpretation of temperature-dependent charge transport measurements in molecular junctions.

Modeling Protein Expression and Protein Signaling Pathways

PubMed Central

Telesca, Donatello; Müller, Peter; Kornblau, Steven M.; Suchard, Marc A.; Ji, Yuan

2015-01-01

High-throughput functional proteomic technologies provide a way to quantify the expression of proteins of interest. Statistical inference centers on identifying the activation state of proteins and their patterns of molecular interaction formalized as dependence structure. Inference on dependence structure is particularly important when proteins are selected because they are part of a common molecular pathway. In that case, inference on dependence structure reveals properties of the underlying pathway. We propose a probability model that represents molecular interactions at the level of hidden binary latent variables that can be interpreted as indicators for active versus inactive states of the proteins. The proposed approach exploits available expert knowledge about the target pathway to define an informative prior on the hidden conditional dependence structure. An important feature of this prior is that it provides an instrument to explicitly anchor the model space to a set of interactions of interest, favoring a local search approach to model determination. We apply our model to reverse-phase protein array data from a study on acute myeloid leukemia. Our inference identifies relevant subpathways in relation to the unfolding of the biological process under study. PMID:26246646

Probing Molecular Mechanisms of the Hsp90 Chaperone: Biophysical Modeling Identifies Key Regulators of Functional Dynamics

PubMed Central

Dixit, Anshuman; Verkhivker, Gennady M.

2012-01-01

Deciphering functional mechanisms of the Hsp90 chaperone machinery is an important objective in cancer biology aiming to facilitate discovery of targeted anti-cancer therapies. Despite significant advances in understanding structure and function of molecular chaperones, organizing molecular principles that control the relationship between conformational diversity and functional mechanisms of the Hsp90 activity lack a sufficient quantitative characterization. We combined molecular dynamics simulations, principal component analysis, the energy landscape model and structure-functional analysis of Hsp90 regulatory interactions to systematically investigate functional dynamics of the molecular chaperone. This approach has identified a network of conserved regions common to the Hsp90 chaperones that could play a universal role in coordinating functional dynamics, principal collective motions and allosteric signaling of Hsp90. We have found that these functional motifs may be utilized by the molecular chaperone machinery to act collectively as central regulators of Hsp90 dynamics and activity, including the inter-domain communications, control of ATP hydrolysis, and protein client binding. These findings have provided support to a long-standing assertion that allosteric regulation and catalysis may have emerged via common evolutionary routes. The interaction networks regulating functional motions of Hsp90 may be determined by the inherent structural architecture of the molecular chaperone. At the same time, the thermodynamics-based “conformational selection” of functional states is likely to be activated based on the nature of the binding partner. This mechanistic model of Hsp90 dynamics and function is consistent with the notion that allosteric networks orchestrating cooperative protein motions can be formed by evolutionary conserved and sparsely connected residue clusters. Hence, allosteric signaling through a small network of distantly connected residue clusters may be a rather general functional requirement encoded across molecular chaperones. The obtained insights may be useful in guiding discovery of allosteric Hsp90 inhibitors targeting protein interfaces with co-chaperones and protein binding clients. PMID:22624053

A Combined Pharmacophore Modeling, 3D QSAR and Virtual Screening Studies on Imidazopyridines as B-Raf Inhibitors

PubMed Central

Xie, Huiding; Chen, Lijun; Zhang, Jianqiang; Xie, Xiaoguang; Qiu, Kaixiong; Fu, Jijun

2015-01-01

B-Raf kinase is an important target in treatment of cancers. In order to design and find potent B-Raf inhibitors (BRIs), 3D pharmacophore models were created using the Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Database (GALAHAD). The best pharmacophore model obtained which was used in effective alignment of the data set contains two acceptor atoms, three donor atoms and three hydrophobes. In succession, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on 39 imidazopyridine BRIs to build three dimensional quantitative structure-activity relationship (3D QSAR) models based on both pharmacophore and docking alignments. The CoMSIA model based on the pharmacophore alignment shows the best result (q2 = 0.621, r2pred = 0.885). This 3D QSAR approach provides significant insights that are useful for designing potent BRIs. In addition, the obtained best pharmacophore model was used for virtual screening against the NCI2000 database. The hit compounds were further filtered with molecular docking, and their biological activities were predicted using the CoMSIA model, and three potential BRIs with new skeletons were obtained. PMID:26035757

A Combined Pharmacophore Modeling, 3D QSAR and Virtual Screening Studies on Imidazopyridines as B-Raf Inhibitors.

PubMed

Xie, Huiding; Chen, Lijun; Zhang, Jianqiang; Xie, Xiaoguang; Qiu, Kaixiong; Fu, Jijun

2015-05-29

B-Raf kinase is an important target in treatment of cancers. In order to design and find potent B-Raf inhibitors (BRIs), 3D pharmacophore models were created using the Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Database (GALAHAD). The best pharmacophore model obtained which was used in effective alignment of the data set contains two acceptor atoms, three donor atoms and three hydrophobes. In succession, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on 39 imidazopyridine BRIs to build three dimensional quantitative structure-activity relationship (3D QSAR) models based on both pharmacophore and docking alignments. The CoMSIA model based on the pharmacophore alignment shows the best result (q(2) = 0.621, r(2)(pred) = 0.885). This 3D QSAR approach provides significant insights that are useful for designing potent BRIs. In addition, the obtained best pharmacophore model was used for virtual screening against the NCI2000 database. The hit compounds were further filtered with molecular docking, and their biological activities were predicted using the CoMSIA model, and three potential BRIs with new skeletons were obtained.

Multi-scale genetic dynamic modelling I : an algorithm to compute generators.

PubMed

Kirkilionis, Markus; Janus, Ulrich; Sbano, Luca

2011-09-01

We present a new approach or framework to model dynamic regulatory genetic activity. The framework is using a multi-scale analysis based upon generic assumptions on the relative time scales attached to the different transitions of molecular states defining the genetic system. At micro-level such systems are regulated by the interaction of two kinds of molecular players: macro-molecules like DNA or polymerases, and smaller molecules acting as transcription factors. The proposed genetic model then represents the larger less abundant molecules with a finite discrete state space, for example describing different conformations of these molecules. This is in contrast to the representations of the transcription factors which are-like in classical reaction kinetics-represented by their particle number only. We illustrate the method by considering the genetic activity associated to certain configurations of interacting genes that are fundamental to modelling (synthetic) genetic clocks. A largely unknown question is how different molecular details incorporated via this more realistic modelling approach lead to different macroscopic regulatory genetic models which dynamical behaviour might-in general-be different for different model choices. The theory will be applied to a real synthetic clock in a second accompanying article (Kirkilioniset al., Theory Biosci, 2011).

Interaction of methotrexate with trypsin analyzed by spectroscopic and molecular modeling methods

NASA Astrophysics Data System (ADS)

Wang, Yanqing; Zhang, Hongmei; Cao, Jian; Zhou, Qiuhua

2013-11-01

Trypsin is one of important digestive enzymes that have intimate correlation with human health and illness. In this work, the interaction of trypsin with methotrexate was investigated by spectroscopic and molecular modeling methods. The results revealed that methotrexate could interact with trypsin with about one binding site. Methotrexate molecule could enter into the primary substrate-binding pocket, resulting in inhibition of trypsin activity. Furthermore, the thermodynamic analysis implied that electrostatic force, hydrogen bonding, van der Waals and hydrophobic interactions were the main interactions for stabilizing the trypsin-methotrexate system, which agreed well with the results from the molecular modeling study.

Novel Gbeta Mimic Kelch Proteins Gpb1 and Gpb2 Connect G-Protein Signaling to Ras via Yeast Neurofibromin Homologs Ira 1 and Ira 2: A Model for Human NF1

DTIC Science & Technology

2006-03-01

Introduction Molecular switches composed of G-protein coupled receptors (GPCRs) and associated heterotrimeric G proteins transduce extracellular stimuli...We are investigating the molecular mechanisms by which the Ras GAP activity of the yeast neurofibromin homologs Ira1/2 is regulated as a model to...NF1 (For reviews, see Dasgupta and Gutmann, 2003; Parada, 2000; Zhu and Parada, 2002). It is therefore critical to elucidate the molecular mechanisms

Inhibition of Metalloprotease Botulinum Serotype A from a Pseudo-Peptide Binding Mode to a Small Molecule that is Active in Primary Neurons

DTIC Science & Technology

2007-02-16

a modeled binding mode for inhibitor 2-mercapto-3-phenylpropionyl-RATKML (Ki 330 nM) was generated, and required the use of a molecular dynamic ...2-mercapto-3-phenylpropionyl-RATKML (K(i) = 330 nM) was generated, and required the use of a molecular dynamic conformer of the enzyme displaying the...SiliconGraphicsOctane 2. Insight II (Accelrys, San Diego, CA) was used to build and inspect models. Energy refinement and molecular dynamics were performed using the

Computer aided drug design

NASA Astrophysics Data System (ADS)

Jain, A.

2017-08-01

Computer based method can help in discovery of leads and can potentially eliminate chemical synthesis and screening of many irrelevant compounds, and in this way, it save time as well as cost. Molecular modeling systems are powerful tools for building, visualizing, analyzing and storing models of complex molecular structure that can help to interpretate structure activity relationship. The use of various techniques of molecular mechanics and dynamics and software in Computer aided drug design along with statistics analysis is powerful tool for the medicinal chemistry to synthesis therapeutic and effective drugs with minimum side effect.

In silico study of in vitro GPCR assays by QSAR modeling ...

EPA Pesticide Factsheets

The U.S. EPA is screening thousands of chemicals of environmental interest in hundreds of in vitro high-throughput screening (HTS) assays (the ToxCast program). One goal is to prioritize chemicals for more detailed analyses based on activity in molecular initiating events (MIE) of adverse outcome pathways (AOPs). However, the chemical space of interest for environmental exposure is much wider than this set of chemicals. Thus, there is a need to fill data gaps with in silico methods, and quantitative structure-activity relationships (QSARs) are a proven and cost effective approach to predict biological activity. ToxCast in turn provides relatively large datasets that are ideal for training and testing QSAR models. The overall goal of the study described here was to develop QSAR models to fill the data gaps in a larger environmental database of ~32k structures. The specific aim of the current work was to build QSAR models for 18 G-Protein Coupled Receptor (GPCR) assays, part of the aminergic category. Two QSAR modeling strategies were adopted: classification models were developed to separate chemicals into active/non-active classes, and then regression models were built to predict the potency values of the bioassays for the active chemicals. Multiple software programs were used to calculate constitutional, topological and substructural molecular descriptors from two-dimensional (2D) chemical structures. Model-fitting methods included PLSDA (partial least squares d

Molecular Indicators of Stress-Induced Neuroinflammation in a Mouse Model Simulating Features of Post-Traumatic Stress Disorder (Open Access)

DTIC Science & Technology

2017-05-23

OPEN ORIGINAL ARTICLE Molecular indicators of stress-induced neuroinflammation in a mouse model simulating features of post -traumatic stress disorder... post -traumatic stress disorder (PTSD). The model involved exposure of an intruder (male C57BL/6) mouse to a resident aggressor (male SJL) mouse for 5...revealed that neurogenesis and synaptic plasticity pathways were activated during the early responses but were inhibited after the later post -trauma

Density functional theory molecular modeling, chemical synthesis, and antimicrobial behaviour of selected benzimidazole derivatives

NASA Astrophysics Data System (ADS)

Marinescu, Maria; Tudorache, Diana Gabriela; Marton, George Iuliu; Zalaru, Christina-Marie; Popa, Marcela; Chifiriuc, Mariana-Carmen; Stavarache, Cristina-Elena; Constantinescu, Catalin

2017-02-01

Eco-friendly, one-pot, solvent-free synthesis of biologically active 2-substituted benzimidazoles is presented and discussed herein. Novel N-Mannich bases are synthesized from benzimidazoles, secondary amines and formaldehyde, and their structures are confirmed by 1H nuclear magnetic resonance (NMR), Fourier transform infrared (FTIR), and elemental analysis. All benzimidazole derivatives are evaluated by qualitative and quantitative methods against 9 bacterial strains. The largest microbicide and anti-biofilm effect is observed for the 2-(1-hydroxyethyl)-compounds. Density functional theory (DFT) modeling of the molecular structure and frontier molecular orbitals, i.e. highest occupied molecular orbital and lowest unoccupied molecular orbital (HOMO/LUMO), is accomplished by using the GAMESS 2012 software. Antimicrobial activity is correlated with the electronic parameters (chemical hardness, electronic chemical potential, global electrophilicity index), Mullikan atomic charges and geometric parameters of the benzimidazole compounds. The planarity of the compound, symmetry of the molecule, and the presence of a nucleophilic group, are advantages for a high antimicrobial activity. Finally, we briefly show that further accurate processing of such compounds into thin films and hybrid structures, e.g. by laser ablation matrix-assisted pulsed laser evaporation and/or laser-induced forward transfer, may indeed provide simple and environmental friendly, state-of-the-art solutions for antimicrobial coatings.

Using Molecular Models To Show Steric Clash in Peptides: An Illustration of Two Disallowed Regions in the Ramachandran Diagram

ERIC Educational Resources Information Center

Halkides, Christopher J.

2013-01-01

In this activity, students manipulate three-dimensional molecular models of the Ala-Ala-Ala tripeptide, where Ala is alanine. They rotate bonds to show that the pairs of dihedral angles phi = 0 degrees, psi = 180 degrees, and phi = 0 degrees, psi = 0 degrees lead to unfavorable interactions among the main chain atoms of the tripeptide. This…

Synthesis, biological evaluation, QSAR study and molecular docking of novel N-(4-amino carbonylpiperazinyl) (thio)phosphoramide derivatives as cholinesterase inhibitors.

PubMed

Gholivand, Khodayar; Ebrahimi Valmoozi, Ali Asghar; Bonsaii, Mahyar

2014-06-01

Novel (thio)phosphoramidate derivatives based on piperidincarboxamide with the general formula of (NH2-C(O)-C5H9N)-P(X=O,S)R1R2 (1-5) and (NH2-C(O)-C5H9N)2-P(O)R (6-9) were synthesized and characterized by (31)P, (13)C, (1)H NMR, IR spectroscopy. Furthermore, the crystal structure of compound (NH2-C(O)-C5H9N)2-P(O)(OC6H5) (6) was investigated. The activities of derivatives on cholinesterases (ChE) were determined using a modified Ellman's method. Also the mixed-type mechanisms of these compounds were evaluated by Lineweaver-Burk plots. Molecular docking and quantitative structure-activity relationship (QSAR) were used to understand the relationship between molecular structural features and anti-ChE activity, and to predict the binding affinity of phosphoramido-piperidinecarboxamides (PAPCAs) to ChE receptors. From molecular docking analysis, noncovalent interactions especially hydrogen bonding as well as hydrophobic was found between PAPCAs and ChE. Based on the docking results, appropriate molecular structural parameters were adopted to develop a QSAR model. DFT-QSAR models for ChE enzymes demonstrated the importance of electrophilicity parameter in describing the anti-AChE and anti-BChE activities of the synthesized compounds. The correlation matrix of QSAR models and docking analysis confirmed that electrophilicity descriptor can control the influence of the hydrophobic properties of P=(O, S) and CO functional groups of PAPCA derivatives in the inhibition of human ChE enzymes. Copyright © 2014 Elsevier Inc. All rights reserved.

Synthesis, hydrolysis rates, supercomputer modeling, and antibacterial activity of bicyclic tetrahydropyridazinones.

PubMed

Jungheim, L N; Boyd, D B; Indelicato, J M; Pasini, C E; Preston, D A; Alborn, W E

1991-05-01

Bicyclic tetrahydropyridazinones, such as 13, where X are strongly electron-withdrawing groups, were synthesized to investigate their antibacterial activity. These delta-lactams are homologues of bicyclic pyrazolidinones 15, which were the first non-beta-lactam containing compounds reported to bind to penicillin-binding proteins (PBPs). The delta-lactam compounds exhibit poor antibacterial activity despite having reactivity comparable to the gamma-lactams. Molecular modeling based on semiempirical molecular orbital calculations on a Cray X-MP supercomputer, predicted that the reason for the inactivity is steric bulk hindering high affinity of the compounds to PBPs, as well as high conformational flexibility of the tetrahydropyridazinone ring hampering effective alignment of the molecule in the active site. Subsequent PBP binding experiments confirmed that this class of compound does not bind to PBPs.

Synthesis, molecular modeling studies and evaluation of antifungal activity of a novel series of thiazole derivatives.

PubMed

Lino, Cleudiomar Inácio; Gonçalves de Souza, Igor; Borelli, Beatriz Martins; Silvério Matos, Thelma Tirone; Santos Teixeira, Iasmin Natália; Ramos, Jonas Pereira; Maria de Souza Fagundes, Elaine; de Oliveira Fernandes, Philipe; Maltarollo, Vinícius Gonçalves; Johann, Susana; de Oliveira, Renata Barbosa

2018-05-10

In the search for new antifungal agents, a novel series of fifteen hydrazine-thiazole derivatives was synthesized and assayed in vitro against six clinically important Candida and Cryptococcus species and Paracoccidioides brasiliensis. Eight compounds showed promising antifungal activity with minimum inhibitory concentration (MIC) values ranging from 0.45 to 31.2 μM, some of them being equally or more active than the drug fluconazole and amphotericin B. Active compounds were additionally tested for toxicity against human embryonic kidney (HEK-293) cells and none of them exhibited significant cytotoxicity, indicating high selectivity. Molecular modeling studies results corroborated experimental SAR results, suggesting their use in the design of new antifungal agents. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Lanthanide and transition metal complexes of bioactive coumarins: molecular modeling and spectroscopic studies.

PubMed

Georgieva, I; Mihaylov, Tz; Trendafilova, N

2014-06-01

The present paper summarizes theoretical and spectroscopic investigations on a series of active coumarins and their lanthanide and transition metal complexes with application in medicine and pharmacy. Molecular modeling as well as IR, Raman, NMR and electronic spectral simulations at different levels of theory were performed to obtain important molecular descriptors: total energy, formation energy, binding energy, stability, conformations, structural parameters, electron density distribution, molecular electrostatic potential, Fukui functions, atomic charges, and reactive indexes. The computations are performed both in gas phase and in solution with consideration of the solvent effect on the molecular structural and energetic parameters. The investigations have shown that the advanced computational methods are reliable for prediction of the metal-coumarin binding mode, electron density distribution, thermodynamic properties as well as the strength and nature of the metal-coumarin interaction (not experimentally accessible) and correctly interpret the experimental spectroscopic data. Known results from biological tests for cytotoxic, antimicrobial, anti-fungal, spasmolytic and anti-HIV activities on the studied metal complexes are reported and discussed. Copyright © 2014 Elsevier Inc. All rights reserved.

Screening of photosynthetic pigments for herbicidal activity with a new computational molecular approach.

PubMed

Krishnaraj, R Navanietha; Chandran, Saravanan; Pal, Parimal; Berchmans, Sheela

2013-12-01

There is an immense interest among the researchers to identify new herbicides which are effective against the herbs without affecting the environment. In this work, photosynthetic pigments are used as the ligands to predict their herbicidal activity. The enzyme 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase is a good target for the herbicides. Homology modeling of the target enzyme is done using Modeler 9.11 and the model is validated. Docking studies were performed with AutoDock Vina algorithm to predict the binding of the natural pigments such as β-carotene, chlorophyll a, chlorophyll b, phycoerythrin and phycocyanin to the target. β-carotene, phycoerythrin and phycocyanin have higher binding energies indicating the herbicidal activity of the pigments. This work reports a procedure to screen herbicides with computational molecular approach. These pigments will serve as potential bioherbicides in the future.

Molecular modeling of human neutral sphingomyelinase provides insight into its molecular interactions.

PubMed

Dinesh; Goswami, Angshumala; Suresh, Panneer Selvam; Thirunavukkarasu, Chinnasamy; Weiergräber, Oliver H; Kumar, Muthuvel Suresh

2011-01-01

The neutral sphingomyelinase (N-SMase) is considered a major candidate for mediating the stress-induced production of ceramide, and it plays an important role in cell-cycle arrest, apoptosis, inflammation, and eukaryotic stress responses. Recent studies have identified a small region at the very N-terminus of the 55 kDa tumour necrosis factor receptor (TNF-R55), designated the neutral sphingomyelinase activating domain (NSD) that is responsible for the TNF-induced activation of N-SMase. There is no direct association between TNF-R55 NSD and N-SMase; instead, a protein named factor associated with N-SMase activation (FAN) has been reported to couple the TNF-R55 NSD to N-SMase. Since the three-dimensional fold of N-SMase is still unknown, we have modeled the structure using the protein fold recognition and threading method. Moreover, we propose models for the TNF-R55 NSD as well as the FAN protein in order to study the structural basis of N-SMase activation and regulation. Protein-protein interaction studies suggest that FAN is crucially involved in mediating TNF-induced activation of the N-SMase pathway, which in turn regulates mitogenic and proinflammatory responses. Inhibition of N-SMase may lead to reduction of ceramide levels and hence may provide a novel therapeutic strategy for inflammation and autoimmune diseases. Molecular dynamics (MD) simulations were performed to check the stability of the predicted model and protein-protein complex; indeed, stable RMS deviations were obtained throughout the simulation. Furthermore, in silico docking of low molecular mass ligands into the active site of N-SMase suggests that His135, Glu48, Asp177, and Asn179 residues play crucial roles in this interaction. Based on our results, these ligands are proposed to be potent and selective N-SMase inhibitors, which may ultimately prove useful as lead compounds for drug development.

Quantitative structure activity relationship studies of mushroom tyrosinase inhibitors

NASA Astrophysics Data System (ADS)

Xue, Chao-Bin; Luo, Wan-Chun; Ding, Qi; Liu, Shou-Zhu; Gao, Xing-Xiang

2008-05-01

Here, we report our results from quantitative structure-activity relationship studies on tyrosinase inhibitors. Interactions between benzoic acid derivatives and tyrosinase active sites were also studied using a molecular docking method. These studies indicated that one possible mechanism for the interaction between benzoic acid derivatives and the tyrosinase active site is the formation of a hydrogen-bond between the hydroxyl (aOH) and carbonyl oxygen atoms of Tyr98, which stabilized the position of Tyr98 and prevented Tyr98 from participating in the interaction between tyrosinase and ORF378. Tyrosinase, also known as phenoloxidase, is a key enzyme in animals, plants and insects that is responsible for catalyzing the hydroxylation of tyrosine into o-diphenols and the oxidation of o-diphenols into o-quinones. In the present study, the bioactivities of 48 derivatives of benzaldehyde, benzoic acid, and cinnamic acid compounds were used to construct three-dimensional quantitative structure-activity relationship (3D-QSAR) models using comparative molecular field (CoMFA) and comparative molecular similarity indices (CoMSIA) analyses. After superimposition using common substructure-based alignments, robust and predictive 3D-QSAR models were obtained from CoMFA ( q 2 = 0.855, r 2 = 0.978) and CoMSIA ( q 2 = 0.841, r 2 = 0.946), with 6 optimum components. Chemical descriptors, including electronic (Hammett σ), hydrophobic (π), and steric (MR) parameters, hydrogen bond acceptor (H-acc), and indicator variable ( I), were used to construct a 2D-QSAR model. The results of this QSAR indicated that π, MR, and H-acc account for 34.9, 31.6, and 26.7% of the calculated biological variance, respectively. The molecular interactions between ligand and target were studied using a flexible docking method (FlexX). The best scored candidates were docked flexibly, and the interaction between the benzoic acid derivatives and the tyrosinase active site was elucidated in detail. We believe that the QSAR models built here provide important information necessary for the design of novel tyrosinase inhibitors.

Produced water re-injection in a non-fresh water aquifer with geochemical reaction, hydrodynamic molecular dispersion and adsorption kinetics controlling: model development and numerical simulation

NASA Astrophysics Data System (ADS)

Obe, Ibidapo; Fashanu, T. A.; Idialu, Peter O.; Akintola, Tope O.; Abhulimen, Kingsley E.

2017-06-01

An improved produced water reinjection (PWRI) model that incorporates filtration, geochemical reaction, molecular transport, and mass adsorption kinetics was developed to predict cake deposition and injectivity performance in hydrocarbon aquifers in Nigeria oil fields. Thus, the improved PWRI model considered contributions of geochemical reaction, adsorption kinetics, and hydrodynamic molecular dispersion mechanism to alter the injectivity and deposition of suspended solids on aquifer wall resulting in cake formation in pores during PWRI and transport of active constituents in hydrocarbon reservoirs. The injectivity decline and cake deposition for specific case studies of hydrocarbon aquifers in Nigeria oil fields were characterized with respect to its well geometry, lithology, and calibrations data and simulated in COMSOL multiphysics software environment. The PWRI model was validated by comparisons to assessments of previous field studies based on data and results supplied by operator and regulator. The results of simulation showed that PWRI performance was altered because of temporal variations and declinations of permeability, injectivity, and cake precipitation, which were observed to be dependent on active adsorption and geochemical reaction kinetics coupled with filtration scheme and molecular dispersion. From the observed results and findings, transition time t r to cake nucleation and growth were dependent on aquifer constituents, well capacity, filtration coefficients, particle-to-grain size ratio, water quality, and more importantly, particle-to-grain adsorption kinetics. Thus, the results showed that injectivity decline and permeability damage were direct contributions of geochemical reaction, hydrodynamic molecular diffusion, and adsorption kinetics to the internal filtration mechanism, which are largely dependent on the initial conditions of concentration of active constituents of produced water and aquifer capacity.

Structural insights of Staphylococcus aureus FtsZ inhibitors through molecular docking, 3D-QSAR and molecular dynamics simulations.

PubMed

Ballu, Srilata; Itteboina, Ramesh; Sivan, Sree Kanth; Manga, Vijjulatha

2018-02-01

Filamentous temperature-sensitive protein Z (FtsZ) is a protein encoded by the FtsZ gene that assembles into a Z-ring at the future site of the septum of bacterial cell division. Structurally, FtsZ is a homolog of eukaryotic tubulin but has low sequence similarity; this makes it possible to obtain FtsZ inhibitors without affecting the eukaryotic cell division. Computational studies were performed on a series of substituted 3-arylalkoxybenzamide derivatives reported as inhibitors of FtsZ activity in Staphylococcus aureus. Quantitative structure-activity relationship models (QSAR) models generated showed good statistical reliability, which is evident from r 2 ncv and r 2 loo values. The predictive ability of these models was determined and an acceptable predictive correlation (r 2 Pred ) values were obtained. Finally, we performed molecular dynamics simulations in order to examine the stability of protein-ligand interactions. This facilitated us to compare free binding energies of cocrystal ligand and newly designed molecule B1. The good concordance between the docking results and comparative molecular field analysis (CoMFA)/comparative molecular similarity indices analysis (CoMSIA) contour maps afforded obliging clues for the rational modification of molecules to design more potent FtsZ inhibitors.

Molecular systems biology of ErbB1 signaling: bridging the gap through multiscale modeling and high-performance computing.

PubMed

Shih, Andrew J; Purvis, Jeremy; Radhakrishnan, Ravi

2008-12-01

The complexity in intracellular signaling mechanisms relevant for the conquest of many diseases resides at different levels of organization with scales ranging from the subatomic realm relevant to catalytic functions of enzymes to the mesoscopic realm relevant to the cooperative association of molecular assemblies and membrane processes. Consequently, the challenge of representing and quantifying functional or dysfunctional modules within the networks remains due to the current limitations in our understanding of mesoscopic biology, i.e., how the components assemble into functional molecular ensembles. A multiscale approach is necessary to treat a hierarchy of interactions ranging from molecular (nm, ns) to signaling (microm, ms) length and time scales, which necessitates the development and application of specialized modeling tools. Complementary to multiscale experimentation (encompassing structural biology, mechanistic enzymology, cell biology, and single molecule studies) multiscale modeling offers a powerful and quantitative alternative for the study of functional intracellular signaling modules. Here, we describe the application of a multiscale approach to signaling mediated by the ErbB1 receptor which constitutes a network hub for the cell's proliferative, migratory, and survival programs. Through our multiscale model, we mechanistically describe how point-mutations in the ErbB1 receptor can profoundly alter signaling characteristics leading to the onset of oncogenic transformations. Specifically, we describe how the point mutations induce cascading fragility mechanisms at the molecular scale as well as at the scale of the signaling network to preferentially activate the survival factor Akt. We provide a quantitative explanation for how the hallmark of preferential Akt activation in cell-lines harboring the constitutively active mutant ErbB1 receptors causes these cell-lines to be addicted to ErbB1-mediated generation of survival signals. Consequently, inhibition of ErbB1 activity leads to a remarkable therapeutic response in the addicted cell lines.

Molecular design and structure--activity relationships leading to the potent, selective, and orally active thrombin active site inhibitor BMS-189664.

PubMed

Das, Jagabandhu; Kimball, S David; Hall, Steven E; Han, Wen Ching; Iwanowicz, Edwin; Lin, James; Moquin, Robert V; Reid, Joyce A; Sack, John S; Malley, Mary F; Chang, Chiehying Y; Chong, Saeho; Wang-Iverson, David B; Roberts, Daniel G M; Seiler, Steven M; Schumacher, William A; Ogletree, Martin L

2002-01-07

A series of structurally novel small molecule inhibitors of human alpha-thrombin was prepared to elucidate their structure-activity relationships (SARs), selectivity and activity in vivo. BMS-189664 (3) is identified as a potent, selective, and orally active reversible inhibitor of human alpha-thrombin which is efficacious in vivo in a mouse lethality model, and at inhibiting both arterial and venous thrombosis in cynomolgus monkey models.

Topological pattern for the search of new active drugs against methicillin resistant Staphylococcus aureus.

PubMed

Bueso-Bordils, Jose I; Perez-Gracia, Maria T; Suay-Garcia, Beatriz; Duart, Maria J; Martin Algarra, Rafael V; Lahuerta Zamora, Luis; Anton-Fos, Gerardo M; Aleman Lopez, Pedro A

2017-09-29

Molecular topology was used to develop a mathematical model capable of classifying compounds according to antimicrobial activity against methicillin resistant Staphylococcus aureus (MRSA). Topological indices were used as structural descriptors and their relation to antimicrobial activity was determined by using linear discriminant analysis. This topological model establishes new structure activity relationships which show that the presence of cyclopropyl, chlorine and ramification pairs at a distance of two bonds favor this activity, while the presence of tertiary amines decreases it. This model was applied to a combinatorial library of a thousand and one 6-fluoroquinolones, from which 117 theoretical active molecules were obtained. The compound 10 and five new quinolones were tested against MRSA. They all showed some activity against MRSA, although compounds 6, 8 and 9 showed anti-MRSA activity similar to ciprofloxacin. This model was also applied to 263 theoretical antibacterial agents described by us in a previous work, from which 34 were predicted as theoretically active. Anti-MRSA activity was found bibliographically in 9 of them (ensuring at least 26% of success), and from the rest, 3 compounds were randomly chosen and tested, finding mitomycin C to be more active than ciprofloxacin. The results demonstrate the utility of the molecular topology approaches for identifying new drugs active against MRSA. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Simplified molecular input line entry system-based: QSAR modelling for MAP kinase-interacting protein kinase (MNK1).

PubMed

Begum, S; Achary, P Ganga Raju

2015-01-01

Quantitative structure-activity relationship (QSAR) models were built for the prediction of inhibition (pIC50, i.e. negative logarithm of the 50% effective concentration) of MAP kinase-interacting protein kinase (MNK1) by 43 potent inhibitors. The pIC50 values were modelled with five random splits, with the representations of the molecular structures by simplified molecular input line entry system (SMILES). QSAR model building was performed by the Monte Carlo optimisation using three methods: classic scheme; balance of correlations; and balance correlation with ideal slopes. The robustness of these models were checked by parameters as rm(2), r(*)m(2), [Formula: see text] and randomisation technique. The best QSAR model based on single optimal descriptors was applied to study in vitro structure-activity relationships of 6-(4-(2-(piperidin-1-yl) ethoxy) phenyl)-3-(pyridin-4-yl) pyrazolo [1,5-a] pyrimidine derivatives as a screening tool for the development of novel potent MNK1 inhibitors. The effects of alkyl group, -OH, -NO2, F, Cl, Br, I, etc. on the IC50 values towards the inhibition of MNK1 were also reported.

Some indazoles reduced the activity of human serum paraoxonase 1, an antioxidant enzyme: in vitro inhibition and molecular modeling studies.

PubMed

Alım, Zuhal; Kılıç, Deryanur; Demir, Yeliz

2018-05-09

Paraoxonase 1 (PON1: EC 3.1.8.1) is a vital antioxidant enzyme against mainly atherosclerosis and many other diseases associated with oxidative stress. Thus, studies related to PON1 have an important place in the pharmacology. In this study, we aimed to evaluate the in vitro inhibition effects of some indazoles on the activity of human PON1. PON1 was purified from human serum with a specific activity of 5000 U/mg and 13.50% yield by using simple chromatographic methods. The indazoles showed K i values in a range of 26.0 ± 3.00-111 ± 31.0 μM against hPON1. All these indazoles exhibited competitive inhibition. In addition, molecular docking studies were performed in order to assess the probable binding mechanisms into the active site of hPON1. Molecular modeling studies confirmed our results. Inhibition of PON1 by indazoles supplies a verification to further consideration of limitation dosage of indazole molecule groups as drug.

A comparison study between different molecular weight polysaccharides derived from Lentinus edodes and their antioxidant activities in vivo.

PubMed

You, Ruxu; Wang, Kaiping; Liu, Jinyu; Liu, Maochang; Luo, Li; Zhang, Yu

2011-12-01

Polysaccharide purified Lentinus edodes (Berk.) Sing (Tricholomataceae) has been reported to attenuate oxidative stress in vitro. This study investigated whether polysaccharides from L. edodes with different molecular weight have protective effects against oxidative stress induced by D-galactose (D-gal) in vivo, and determined the specific relationship between molecular weight and antioxidant activity. In the present study, we successfully obtained three purified polysaccharides, coded as LT1, LT2, and LT3, and their molecular weights were 25.5, 306.2, and 605.4 kDa, respectively. The D-gal-treated mice received three polysaccharides once daily for 60 days. The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), the content of malondialdehyde (MDA), and erythrocyte membrane fluidity were measured to evaluate the changes of the antioxidant ability. It was demonstrated that the administration of LT1, LT2, and LT3 could improve the antioxidant status to different levels. Furthermore, LT2 exhibited the highest antioxidant ability among these samples in vivo. Indeed, LT2 significantly decreased the content of MDA in liver (15.91 ± 0.31 versus 23.79 ± 1.18 nmol/mg protein for the model group, p < 0.05), enhanced the fluidity of erythrocyte membrane (2.458 ± 0.023 versus 2.167 ± 0.024 for the model group, p < 0.05), and increased the activities of SOD (147.19 ± 4.90 versus 82.26 ± 5.55 units/mg protein for the model group, p < 0.05) and GSH-Px (310.91 ± 6.24 versus 243.64 ± 6.77 units/mg protein for the model group, p < 0.05) in liver. The LT2 had a potential to be used as a novel natural antioxidant.

From Molecular Docking to 3D-Quantitative Structure-Activity Relationships (3D-QSAR): Insights into the Binding Mode of 5-Lipoxygenase Inhibitors.

PubMed

Eren, Gokcen; Macchiarulo, Antonio; Banoglu, Erden

2012-02-01

Pharmacological intervention with 5-Lipoxygenase (5-LO) is a promising strategy for treatment of inflammatory and allergic ailments, including asthma. With the aim of developing predictive models of 5-LO affinity and gaining insights into the molecular basis of ligand-target interaction, we herein describe QSAR studies of 59 diverse nonredox-competitive 5-LO inhibitors based on the use of molecular shape descriptors and docking experiments. These studies have successfully yielded a predictive model able to explain much of the variance in the activity of the training set compounds while predicting satisfactorily the 5-LO inhibitory activity of an external test set of compounds. The inspection of the selected variables in the QSAR equation unveils the importance of specific interactions which are observed from docking experiments. Collectively, these results may be used to design novel potent and selective nonredox 5-LO inhibitors. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Predicting human skin absorption of chemicals: development of a novel quantitative structure activity relationship.

PubMed

Luo, Wen; Medrek, Sarah; Misra, Jatin; Nohynek, Gerhard J

2007-02-01

The objective of this study was to construct and validate a quantitative structure-activity relationship model for skin absorption. Such models are valuable tools for screening and prioritization in safety and efficacy evaluation, and risk assessment of drugs and chemicals. A database of 340 chemicals with percutaneous absorption was assembled. Two models were derived from the training set consisting 306 chemicals (90/10 random split). In addition to the experimental K(ow) values, over 300 2D and 3D atomic and molecular descriptors were analyzed using MDL's QsarIS computer program. Subsequently, the models were validated using both internal (leave-one-out) and external validation (test set) procedures. Using the stepwise regression analysis, three molecular descriptors were determined to have significant statistical correlation with K(p) (R2 = 0.8225): logK(ow), X0 (quantification of both molecular size and the degree of skeletal branching), and SsssCH (count of aromatic carbon groups). In conclusion, two models to estimate skin absorption were developed. When compared to other skin absorption QSAR models in the literature, our model incorporated more chemicals and explored a large number of descriptors. Additionally, our models are reasonably predictive and have met both internal and external statistical validations.

An undergraduate laboratory activity on molecular dynamics simulations.

PubMed

Spitznagel, Benjamin; Pritchett, Paige R; Messina, Troy C; Goadrich, Mark; Rodriguez, Juan

2016-01-01

Vision and Change [AAAS, 2011] outlines a blueprint for modernizing biology education by addressing conceptual understanding of key concepts, such as the relationship between structure and function. The document also highlights skills necessary for student success in 21st century Biology, such as the use of modeling and simulation. Here we describe a laboratory activity that allows students to investigate the dynamic nature of protein structure and function through the use of a modeling technique known as molecular dynamics (MD). The activity takes place over two lab periods that are 3 hr each. The first lab period unpacks the basic approach behind MD simulations, beginning with the kinematic equations that all bioscience students learn in an introductory physics course. During this period students are taught rudimentary programming skills in Python while guided through simple modeling exercises that lead up to the simulation of the motion of a single atom. In the second lab period students extend concepts learned in the first period to develop skills in the use of expert MD software. Here students simulate and analyze changes in protein conformation resulting from temperature change, solvation, and phosphorylation. The article will describe how these activities can be carried out using free software packages, including Abalone and VMD/NAMD. © 2016 The International Union of Biochemistry and Molecular Biology.

Homology modelling, molecular docking, and molecular dynamics simulations reveal the inhibition of Leishmania donovani dihydrofolate reductase-thymidylate synthase enzyme by Withaferin-A.

PubMed

Vadloori, Bharadwaja; Sharath, A K; Prabhu, N Prakash; Maurya, Radheshyam

2018-04-16

Present in silico study was carried out to explore the mode of inhibition of Leishmania donovani dihydrofolate reductase-thymidylate synthase (Ld DHFR-TS) enzyme by Withaferin-A, a withanolide isolated from Withania somnifera. Withaferin-A (WA) is known for its profound multifaceted properties, but its antileishmanial activity is not well understood. The parasite's DHFR-TS enzyme is diverse from its mammalian host and could be a potential drug target in parasites. A 3D model of Ld DHFR-TS enzyme was built and verified using Ramachandran plot and SAVES tools. The protein was docked with WA-the ligand, methotrexate (MTX)-competitive inhibitor of DHFR, and dihydrofolic acid (DHFA)-substrate for DHFR-TS. Molecular docking studies reveal that WA competes for active sites of both Hu DHFR and TS enzymes whereas it binds to a site other than active site in Ld DHFR-TS. Moreover, Lys 173 residue of DHFR-TS forms a H-bond with WA and has higher binding affinity to Ld DHFR-TS than Hu DHFR and Hu TS. The MD simulations confirmed the H-bonding interactions were stable. The binding energies of WA with Ld DHFR-TS were calculated using MM-PBSA. Homology modelling, molecular docking and MD simulations of Ld DHFR-TS revealed that WA could be a potential anti-leishmanial drug.

Molecular-orbital models for the catalytic activity and selectivity of coordinatively unsaturated platinum surfaces and complexes

NASA Astrophysics Data System (ADS)

Balazs, A. C.; Johnson, K. H.

1982-01-01

Electronic structures have been calculated for 5-, 6-, and 10-atom Pt clusters, as well as for a Pt(PH 3) 4 coordination complex, using the self-consistent-field X-alpha scattered-wave (SCF-Xα-SW) molecular-orbital technique. The 10-atom cluster models the local geometry of a flat, unreconstructed Pt(100) surface, while the 5- and 6-atom clusters show features of a stepped Pt surface. Pt(PH 3) 4 resembles the chemically similar homogeneous catalyst Pt(PPh 3) 4. Common to all these coordinatively unsaturated complexes are orbitals lying near or coinciding with the highest occupied molecular orbital ("Fermi level") which show pronounced d lobes pointing directly into the vacuum. Under the hypothesis that these molecular orbitals are mainly responsible for the chemical activities of the above species, one can account for the relative similarities and differences in catalytic activity and selectivity displayed by unreconstructed Pt(100) surfaces, stepped Pt surfaces or particles, and isolated Pt(PPh 3) 4 coordination complexes. The relevance of these findings to catalyst-support interactions is also discussed. Finally, relativistic corrections to the electronic structures are calculated and their implications on catalytic properties discussed.

Prostaglandins, steroids and reception (an attempt to model the structure of the active centers of adrenoreception).

PubMed

Podymov, V K; Piruzyan, L A; Gladkikh, S P; Kats, M M; Nizhnii, S V

1980-01-01

On the basis of numerous results of investigations on adrenergic systems, an orientational model of the adrenoreceptor (AR) is postulated. Its active center includes low-molecular-weight components--prostaglandins (PGE, PGF), steroids (cortisone, hydrocortisone), S+-adenosylmethionine, Ca, Mg, and Mn ions. Appraisal of the stereospecific characteristics of such a functional unit of AR explains the difference in the nature and magnitude of the effects of interaction of the catecholamines, their agonists and antagonists will the so-called alpha- and beta-AR. Depending on the organ or tissue in which the AR is located, its protein subunits comprise adenylcyclase (beta-AR) or Na,K-ATPase (alpha-AR). An obligatory component of the AR is catechol-O-methyltransferase. The model elaborated describes satisfactorily the molecular mechanisms of action of many pharmacological agents, explains why attempts to isolate and reconstruct the AR have proved fruitless, and gives grounds for rejecting the hypothesis that there exist steroid, prostaglandin, and purinergic receptors, linking the exceptionally high and diverse activity of these biologically active substances with their participation in adrenoreception among other reasons. A conception of the active centers of the AR as low-molecular-weight entities permits the explanation of such phenomena as the desensitization of the AR, the "interconversion" of beta-AR into alpha-AR with a change in the parameters of the medium, and certain components of the pathogenesis of bronchial asthma, etc.

Constitutively active mutants of the alpha 1B-adrenergic receptor: role of highly conserved polar amino acids in receptor activation.

PubMed Central

Scheer, A; Fanelli, F; Costa, T; De Benedetti, P G; Cotecchia, S

1996-01-01

Site-directed mutagenesis and molecular dynamics simulations of the alpha 1B-adrenergic receptor (AR) were combined to explore the potential molecular changes correlated with the transition from R (inactive state) to R (active state). Using molecular dynamics analysis we compared the structural/dynamic features of constitutively active mutants with those of the wild type and of an inactive alpha 1B-AR to build a theoretical model which defines the essential features of R and R. The results of site-directed mutagenesis were in striking agreement with the predictions of the model supporting the following hypothesis. (i) The equilibrium between R and R depends on the equilibrium between the deprotonated and protonated forms, respectively, of D142 of the DRY motif. In fact, replacement of D142 with alanine confers high constitutive activity to the alpha 1B-AR. (ii) The shift of R143 of the DRY sequence out of a conserved 'polar pocket' formed by N63, D91, N344 and Y348 is a feature common to all the active structures, suggesting that the role of R143 is fundamental for mediating receptor activation. Disruption of these intramolecular interactions by replacing N63 with alanine constitutively activates the alpha 1B-AR. Our findings might provide interesting generalities about the activation process of G protein-coupled receptors. Images PMID:8670860

Structure-activity relationships for novel drug precursor N-substituted-6-acylbenzothiazolon derivatives: A theoretical approach

NASA Astrophysics Data System (ADS)

Sıdır, Yadigar Gülseven; Sıdır, İsa

2013-08-01

In this study, the twelve new modeled N-substituted-6-acylbenzothiazolon derivatives having analgesic analog structure have been investigated by quantum chemical methods using a lot of electronic parameters and structure-activity properties; such as molecular polarizability (α), dipole moment (μ), EHOMO, ELUMO, q-, qH+, molecular volume (Vm), ionization potential (IP), electron affinity (EA), electronegativity (χ), molecular hardness (η), molecular softness (S), electrophilic index (ω), heat of formation (HOF), molar refractivity (MR), octanol-water partition coefficient (log P), thermochemical properties (entropy (S), capacity of heat (Cv)); as to investigate activity relationships with molecular structure. The correlations of log P with Vm, MR, ω, EA, EHOMO - ELUMO (ΔE), HOF in aqueous phase, χ, μ, S, η parameters, respectively are obtained, while the linear relation of log P with IP, Cv, HOF in gas phase are not observed. The log P parameter is obtained to be depending on different properties of compounds due to their complexity.

Pop-it beads to introduce catalysis of reaction rate and substrate depletion effects.

PubMed

Gehret, Austin U

2017-03-04

A kinesthetic classroom activity was designed to help students understand enzyme activity and catalysis of reaction rate. Students served the role of enzymes by manipulating Pop-It Beads as the catalytic event. This activity illuminates the relationship between reaction rate and reaction progress by allowing students to experience first-hand the effect of substrate depletion on catalyzed reaction rate. Preliminary findings based on survey results and exam performance suggest the activity could prove beneficial to students in the targeted learning outcomes. Unique to previous kinesthetic approaches that model Michaelis-Menten kinetics, this activity models the effects of substrate depletion on catalyzed reaction rate. Therefore, it could prove beneficial for conveying the reasoning behind the initial rate simplification used in Michaelis-Menten kinetics. © 2016 by The International Union of Biochemistry and Molecular Biology, 45(2):179-183, 2017. © 2016 The International Union of Biochemistry and Molecular Biology.

Synthesis, biological activity and molecular modeling of 4-fluoro-N-[ω-(1,2,3,4-tetrahydroacridin-9-ylamino)-alkyl]-benzamide derivatives as cholinesterase inhibitors.

PubMed

Szymański, P; Markowicz, M; Bajda, M; Malawska, B; Mikiciuk-Olasik, E

2012-12-01

The aim of this study was to synthesize and determine the biological activity of new derivatives of 4-fluorobenzoic acid and tetrahydroacridine towards inhibition of cholinesterases. Compounds were synthesized in condensation reaction between 9-aminoalkyl-tetrahydroacridines and the activated 4-fluorobenzoic acid. Properties towards inhibition of acetyl- and butyrylcholinesterase were estimated according to Ellman's spectrophotometric method. Among synthesized compounds the most active were compounds 4a and 4d. These compounds, in comparison with tacrine, were characterized by the similar values of IC50. Among all obtained compounds, 4d presented the highest selectivity towards inhibition of acetylcholinesterase. Molecular modeling studies revealed that all derivatives presented similar extended conformation in the gorge of acetylcholinesterase, however, there were 2 main conformations in the active center of butyrylcholinesterase: bent and extended conformation. © Georg Thieme Verlag KG Stuttgart · New York.

Atomistic characterization of the active-site solvation dynamics of a model photocatalyst

DOE PAGES

van Driel, Tim B.; Kjær, Kasper S.; Hartsock, Robert W.; ...

2016-11-28

The interactions between the reactive excited state of molecular photocatalysts and surrounding solvent dictate reaction mechanisms and pathways, but are not readily accessible to conventional optical spectroscopic techniques. Here we report an investigation of the structural and solvation dynamics following excitation of a model photocatalytic molecular system [Ir 2(dimen) 4] 2+, where dimen is para-diisocyanomenthane. The time-dependent structural changes in this model photocatalyst, as well as the changes in the solvation shell structure, have been measured with ultrafast diffuse X-ray scattering and simulated with Born-Oppenheimer Molecular Dynamics. Both methods provide direct access to the solute–solvent pair distribution function, enabling themore » solvation dynamics around the catalytically active iridium sites to be robustly characterized. Our results provide evidence for the coordination of the iridium atoms by the acetonitrile solvent and demonstrate the viability of using diffuse X-ray scattering at free-electron laser sources for studying the dynamics of photocatalysis.« less

Versatile Molecular Functionalization for Inhibiting Concentration Quenching of Thermally Activated Delayed Fluorescence.

PubMed

Lee, Jiyoung; Aizawa, Naoya; Numata, Masaki; Adachi, Chihaya; Yasuda, Takuma

2017-01-01

Concentration quenching of thermally activated delayed fluorescence is found to be dominated by electron-exchange interactions, as described by the Dexter energy-transfer model. Owing to the short-range nature of the electron-exchange interactions, even a small modulation in the molecular geometric structure drastically affects the concentration-quenching, leading to enhanced solid-state photoluminescence and electroluminescence quantum efficiencies. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

North Carolina Biomolecular Engineering and Materials Applications Center (NC-BEMAC).

DTIC Science & Technology

1987-12-29

enzyme has been replaced with cobalt(II). A further objective was to investigate Co2 activation by low molecular weight transition metal complexes as...Characterization of Low Molecular Weight Metal Complexes as Potential Models for IBio-Catalytic Processes. A number of transit ion met~~il oom~pi cxe; hive...binding, the enzyme suffered loss of activity during radiation polymerization. When covalent binding was u:sed it was necessary to introduce suitably

Proposing Novel MAO-B Hit Inhibitors Using Multidimensional Molecular Modeling Approaches and Application of Binary QSAR Models for Prediction of Their Therapeutic Activity, Pharmacokinetic and Toxicity Properties.

PubMed

Is, Yusuf Serhat; Durdagi, Serdar; Aksoydan, Busecan; Yurtsever, Mine

2018-05-07

Monoamine oxidase (MAO) enzymes MAO-A and MAO-B play a critical role in the metabolism of monoamine neurotransmitters. Hence, MAO inhibitors are very important for the treatment of several neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). In this study, 256 750 molecules from Otava Green Chemical Collection were virtually screened for their binding activities as MAO-B inhibitors. Two hit molecules were identified after applying different filters such as high docking scores and selectivity to MAO-B, desired pharmacokinetic profile predictions with binary quantitative structure-activity relationship (QSAR) models. Therapeutic activity prediction as well as pharmacokinetic and toxicity profiles were investigated using MetaCore/MetaDrug platform which is based on a manually curated database of molecular interactions, molecular pathways, gene-disease associations, chemical metabolism, and toxicity information. Particular therapeutic activity and toxic effect predictions are based on the ChemTree ability to correlate structural descriptors to that property using recursive partitioning algorithm. Molecular dynamics (MD) simulations were also performed to make more detailed assessments beyond docking studies. All these calculations were made not only to determine if studied molecules possess the potential to be a MAO-B inhibitor but also to find out whether they carry MAO-B selectivity versus MAO-A. The evaluation of docking results and pharmacokinetic profile predictions together with the MD simulations enabled us to identify one hit molecule (ligand 1, Otava ID: 3463218) which displayed higher selectivity toward MAO-B than a positive control selegiline which is a commercially used drug for PD therapeutic purposes.

Combined 3D-QSAR, molecular docking, molecular dynamics simulation, and binding free energy calculation studies on the 5-hydroxy-2H-pyridazin-3-one derivatives as HCV NS5B polymerase inhibitors.

PubMed

Yu, Haijing; Fang, Yu; Lu, Xia; Liu, Yongjuan; Zhang, Huabei

2014-01-01

The NS5B RNA-dependent RNA polymerase (RdRP) is a promising therapeutic target for developing novel anti-hepatitis C virus (HCV) drugs. In this work, a combined molecular modeling study was performed on a series of 193 5-hydroxy-2H-pyridazin-3-one derivatives as inhibitors of HCV NS5B Polymerase. The best 3D-QSAR models, including CoMFA and CoMSIA, are based on receptor (or docking). Furthermore, a 40-ns molecular dynamics (MD) simulation and binding free energy calculations using docked structures of NS5B with ten compounds, which have diverse structures and pIC50 values, were employed to determine the detailed binding process and to compare the binding modes of the inhibitors with different activities. On one side, the stability and rationality of molecular docking and 3D-QSAR results were validated by MD simulation. The binding free energies calculated by the MM-PBSA method gave a good correlation with the experimental biological activity. On the other side, by analyzing some differences between the molecular docking and the MD simulation results, we can find that the MD simulation could also remedy the defects of molecular docking. The analyses of the combined molecular modeling results have identified that Tyr448, Ser556, and Asp318 are the key amino acid residues in the NS5B binding pocket. The results from this study can provide some insights into the development of novel potent NS5B inhibitors. © 2013 John Wiley & Sons A/S.

Design, synthesis and molecular modeling studies of novel thiazolidine-2,4-dione derivatives as potential anti-cancer agents

NASA Astrophysics Data System (ADS)

Asati, Vivek; Bharti, Sanjay Kumar

2018-02-01

A series of novel thiazolidine-2,4-dione derivatives 4a-x have been designed, synthesized and evaluated for potential anti-cancer activity. The anti-cancer activity of synthesized compounds 4a-x were evaluated against selected human cancer cell line of breast (MCF-7) using sulforhodamine B (SRB) method. Among the synthesized compounds, 4x having 2-cyano phenyl group showed significant cytotoxic activity which is comparable to that of adriamycin as standard anti-cancer drug. The SAR study revealed that the substituted phenyl group on oxadiazole ring attached to thiazolidine-2,4-dione moiety showed significant growth inhibitory activity against MCF-7 cell line. The result of molecular modeling studies showed that compounds 4f, 4o and 4x having similar structural alignment as crystal ligand of protein.

QSAR and docking studies on xanthone derivatives for anticancer activity targeting DNA topoisomerase IIα

PubMed Central

Alam, Sarfaraz; Khan, Feroz

2014-01-01

Due to the high mortality rate in India, the identification of novel molecules is important in the development of novel and potent anticancer drugs. Xanthones are natural constituents of plants in the families Bonnetiaceae and Clusiaceae, and comprise oxygenated heterocycles with a variety of biological activities along with an anticancer effect. To explore the anticancer compounds from xanthone derivatives, a quantitative structure activity relationship (QSAR) model was developed by the multiple linear regression method. The structure–activity relationship represented by the QSAR model yielded a high activity–descriptors relationship accuracy (84%) referred by regression coefficient (r2=0.84) and a high activity prediction accuracy (82%). Five molecular descriptors – dielectric energy, group count (hydroxyl), LogP (the logarithm of the partition coefficient between n-octanol and water), shape index basic (order 3), and the solvent-accessible surface area – were significantly correlated with anticancer activity. Using this QSAR model, a set of virtually designed xanthone derivatives was screened out. A molecular docking study was also carried out to predict the molecular interaction between proposed compounds and deoxyribonucleic acid (DNA) topoisomerase IIα. The pharmacokinetics parameters, such as absorption, distribution, metabolism, excretion, and toxicity, were also calculated, and later an appraisal of synthetic accessibility of organic compounds was carried out. The strategy used in this study may provide understanding in designing novel DNA topoisomerase IIα inhibitors, as well as for other cancer targets. PMID:24516330

Biotechnology and genetic engineering in the new drug development. Part III. Biocatalysis, metabolic engineering and molecular modelling.

PubMed

Stryjewska, Agnieszka; Kiepura, Katarzyna; Librowski, Tadeusz; Lochyński, Stanisław

2013-01-01

Industrial biotechnology has been defined as the use and application of biotechnology for the sustainable processing and production of chemicals, materials and fuels. It makes use of biocatalysts such as microbial communities, whole-cell microorganisms or purified enzymes. In the review these processes are described. Drug design is an iterative process which begins when a chemist identifies a compound that displays an interesting biological profile and ends when both the activity profile and the chemical synthesis of the new chemical entity are optimized. Traditional approaches to drug discovery rely on a stepwise synthesis and screening program for large numbers of compounds to optimize activity profiles. Over the past ten to twenty years, scientists have used computer models of new chemical entities to help define activity profiles, geometries and relativities. This article introduces inter alia the concepts of molecular modelling and contains references for further reading.

[Screen potential CYP450 2E1 inhibitors from Chinese herbal medicine based on support vector regression and molecular docking method].

PubMed

Chen, Xi; Lu, Fang; Jiang, Lu-di; Cai, Yi-Lian; Li, Gong-Yu; Zhang, Yan-Ling

2016-07-01

Inhibition of cytochrome P450 (CYP450) enzymes is the most common reasons for drug interactions, so the study on early prediction of CYPs inhibitors can help to decrease the incidence of adverse reactions caused by drug interactions.CYP450 2E1(CYP2E1), as a key role in drug metabolism process, has broad spectrum of drug metabolism substrate. In this study, 32 CYP2E1 inhibitors were collected for the construction of support vector regression (SVR) model. The test set data were used to verify CYP2E1 quantitative models and obtain the optimal prediction model of CYP2E1 inhibitor. Meanwhile, one molecular docking program, CDOCKER, was utilized to analyze the interaction pattern between positive compounds and active pocket to establish the optimal screening model of CYP2E1 inhibitors.SVR model and molecular docking prediction model were combined to screen traditional Chinese medicine database (TCMD), which could improve the calculation efficiency and prediction accuracy. 6 376 traditional Chinese medicine (TCM) compounds predicted by SVR model were obtained, and in further verification by using molecular docking model, 247 TCM compounds with potential inhibitory activities against CYP2E1 were finally retained. Some of them have been verified by experiments. The results demonstrated that this study could provide guidance for the virtual screening of CYP450 inhibitors and the prediction of CYPs-mediated DDIs, and also provide references for clinical rational drug use. Copyright© by the Chinese Pharmaceutical Association.

ABO/Rh Blood-Typing Model: A Problem-Solving Activity

ERIC Educational Resources Information Center

Wake, Carol

2005-01-01

An ARO/Rh Blood-Typing kit useful for students to visualize blood-typing activities and practice problem-solving skills with transfusion reactions is presented. The model also enables students to identify relationships between A, B, and Rh antigens and antibodies in blood and to understand molecular mechanisms involved in transfusion agglutination…

Abiotic stresses activate a MAPkinase in the model grass species Lolium temulentum L.

USDA-ARS?s Scientific Manuscript database

Forage and turf grasses are utilized in diverse environments which exposes them to a variety of abiotic stresses, however very little is known concerning the perception or molecular responses to these various stresses. In the model grass species Lolium temulentum (Lt), a 46 kDa mitogen-activated pro...

Pharmacophore generation, atom-based 3D-QSAR, molecular docking and molecular dynamics simulation studies on benzamide analogues as FtsZ inhibitors.

PubMed

Tripathy, Swayansiddha; Azam, Mohammed Afzal; Jupudi, Srikanth; Sahu, Susanta Kumar

2017-10-11

FtsZ is an appealing target for the design of antimicrobial agent that can be used to defeat the multidrug-resistant bacterial pathogens. Pharmacophore modelling, molecular docking and molecular dynamics (MD) simulation studies were performed on a series of three-substituted benzamide derivatives. In the present study a five-featured pharmacophore model with one hydrogen bond acceptors, one hydrogen bond donors, one hydrophobic and two aromatic rings was developed using 97 molecules having MIC values ranging from .07 to 957 μM. A statistically significant 3D-QSAR model was obtained using this pharmacophore hypothesis with a good correlation coefficient (R 2  = .8319), cross validated coefficient (Q 2  = .6213) and a high Fisher ratio (F = 103.9) with three component PLS factor. A good correlation between experimental and predicted activity of the training (R 2  = .83) and test set (R 2  = .67) molecules were displayed by ADHRR.1682 model. The generated model was further validated by enrichment studies using the decoy test and MAE-based criteria to measure the efficiency of the model. The docking studies of all selected inhibitors in the active site of FtsZ protein showed crucial hydrogen bond interactions with Val 207, Asn 263, Leu 209, Gly 205 and Asn-299 residues. The binding free energies of these inhibitors were calculated by the molecular mechanics/generalized born surface area VSGB 2.0 method. Finally, a 15 ns MD simulation was done to confirm the stability of the 4DXD-ligand complex. On a wider scope, the prospect of present work provides insight in designing molecules with better selective FtsZ inhibitory potential.

Surface enhanced Raman optical activity of molecules on orientationally averaged substrates: theory of electromagnetic effects.

PubMed

Janesko, Benjamin G; Scuseria, Gustavo E

2006-09-28

We present a model for electromagnetic enhancements in surface enhanced Raman optical activity (SEROA) spectroscopy. The model extends previous treatments of SEROA to substrates, such as metal nanoparticles in solution, that are orientationally averaged with respect to the laboratory frame. Our theoretical treatment combines analytical expressions for unenhanced Raman optical activity with molecular polarizability tensors that are dressed by the substrate's electromagnetic enhancements. We evaluate enhancements from model substrates to determine preliminary scaling laws and selection rules for SEROA. We find that dipolar substrates enhance Raman optical activity (ROA) scattering less than Raman scattering. Evanescent gradient contributions to orientationally averaged ROA scale to first or higher orders in the gradient of the incident plane-wave field. These evanescent gradient contributions may be large for substrates with quadrupolar responses to the plane-wave field gradient. Some substrates may also show a ROA contribution that depends only on the molecular electric dipole-electric dipole polarizability. These conclusions are illustrated via numerical calculations of surface enhanced Raman and ROA spectra from (R)-(-)-bromochlorofluoromethane on various model substrates.

EPAs Virtual Embryo: Modeling Developmental Toxicity

EPA Science Inventory

Embryogenesis is regulated by concurrent activities of signaling pathways organized into networks that control spatial patterning, molecular clocks, morphogenetic rearrangements and cell differentiation. Quantitative mathematical and computational models are needed to better unde...

Quantitative structure-activity relationships (QSAR) of some 2,2-diphenyl propionate (DPP) derivatives of muscarinic antagonists

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gordon, R.K.; Breuer, E.; Padilla, F.N.

1987-05-01

QSAR between biological activities and molecular-chemical properties were investigated to aid in designing more effective and potent antimuscarinic pharmacophores. A molecular modeling program was used to calculate geometrical and topological values of a series of DPP pharmacophores. The newly synthesized pharmacophores were tested for their antagonist activities by: (1) inhibition of (N-methyl-/sup 3/H)scopolamine binding assay to the muscarinic receptors of N4TG1 neuroblastoma cells; (2) blocking of acetylcholine-induced contraction of guinea pig ileum; and (3) inhibition of carbachol-induced ..cap alpha..-amylase release from rat pancreas. The differences in the log of these biological activities were directly and significantly related to the distancesmore » between the carbonyl oxygen of the DPP and the quaternary nitrogen of the modified pharmacophores. The biological activities, while depending on each particular assay, varied between three and four logs of activity. The charge remained the same in all the pharmacophores. There were no QSAR correlations between molecular volume, molecular connectivity, or principle moments and their antagonistic activities, although multivariate QSAR was not employed. Thus, based on distance geometry, potent muscarinic pharmacophores can be predicted.« less

Molecular Modeling Studies of 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors through Receptor-Based 3D-QSAR and Molecular Dynamics Simulations.

PubMed

Qian, Haiyan; Chen, Jiongjiong; Pan, Youlu; Chen, Jianzhong

2016-09-19

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a potential target for the treatment of numerous human disorders, such as diabetes, obesity, and metabolic syndrome. In this work, molecular modeling studies combining molecular docking, 3D-QSAR, MESP, MD simulations and free energy calculations were performed on pyridine amides and 1,2,4-triazolopyridines as 11β-HSD1 inhibitors to explore structure-activity relationships and structural requirement for the inhibitory activity. 3D-QSAR models, including CoMFA and CoMSIA, were developed from the conformations obtained by docking strategy. The derived pharmacophoric features were further supported by MESP and Mulliken charge analyses using density functional theory. In addition, MD simulations and free energy calculations were employed to determine the detailed binding process and to compare the binding modes of inhibitors with different bioactivities. The binding free energies calculated by MM/PBSA showed a good correlation with the experimental biological activities. Free energy analyses and per-residue energy decomposition indicated the van der Waals interaction would be the major driving force for the interactions between an inhibitor and 11β-HSD1. These unified results may provide that hydrogen bond interactions with Ser170 and Tyr183 are favorable for enhancing activity. Thr124, Ser170, Tyr177, Tyr183, Val227, and Val231 are the key amino acid residues in the binding pocket. The obtained results are expected to be valuable for the rational design of novel potent 11β-HSD1 inhibitors.

De Novo Design of Bioactive Small Molecules by Artificial Intelligence.

PubMed

Merk, Daniel; Friedrich, Lukas; Grisoni, Francesca; Schneider, Gisbert

2018-01-01

Generative artificial intelligence offers a fresh view on molecular design. We present the first-time prospective application of a deep learning model for designing new druglike compounds with desired activities. For this purpose, we trained a recurrent neural network to capture the constitution of a large set of known bioactive compounds represented as SMILES strings. By transfer learning, this general model was fine-tuned on recognizing retinoid X and peroxisome proliferator-activated receptor agonists. We synthesized five top-ranking compounds designed by the generative model. Four of the compounds revealed nanomolar to low-micromolar receptor modulatory activity in cell-based assays. Apparently, the computational model intrinsically captured relevant chemical and biological knowledge without the need for explicit rules. The results of this study advocate generative artificial intelligence for prospective de novo molecular design, and demonstrate the potential of these methods for future medicinal chemistry. © 2018 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

3D-QSAR and molecular docking studies on designing inhibitors of the hepatitis C virus NS5B polymerase

NASA Astrophysics Data System (ADS)

Li, Wenlian; Si, Hongzong; Li, Yang; Ge, Cuizhu; Song, Fucheng; Ma, Xiuting; Duan, Yunbo; Zhai, Honglin

2016-08-01

Viral hepatitis C infection is one of the main causes of the hepatitis after blood transfusion and hepatitis C virus (HCV) infection is a global health threat. The HCV NS5B polymerase, an RNA dependent RNA polymerase (RdRp) and an essential role in the replication of the virus, has no functional equivalent in mammalian cells. So the research and development of efficient NS5B polymerase inhibitors provides a great strategy for antiviral therapy against HCV. A combined three-dimensional quantitative structure-activity relationship (QSAR) modeling was accomplished to profoundly understand the structure-activity correlation of a train of indole-based inhibitors of the HCV NS5B polymerase to against HCV. A comparative molecular similarity indices analysis (COMSIA) model as the foundation of the maximum common substructure alignment was developed. The optimum model exhibited statistically significant results: the cross-validated correlation coefficient q2 was 0.627 and non-cross-validated r2 value was 0.943. In addition, the results of internal validations of bootstrapping and Y-randomization confirmed the rationality and good predictive ability of the model, as well as external validation (the external predictive correlation coefficient rext2 = 0.629). The information obtained from the COMSIA contour maps enables the interpretation of their structure-activity relationship. Furthermore, the molecular docking study of the compounds for 3TYV as the protein target revealed important interactions between active compounds and amino acids, and several new potential inhibitors with higher activity predicted were designed basis on our analyses and supported by the simulation of molecular docking. Meanwhile, the OSIRIS Property Explorer was introduced to help select more satisfactory compounds. The satisfactory results from this study may lay a reliable theoretical base for drug development of hepatitis C virus NS5B polymerase inhibitors.

Novel ligands of Choline Acetyltransferase designed by in silico molecular docking, hologram QSAR and lead optimization

NASA Astrophysics Data System (ADS)

Kumar, Rajnish; Långström, Bengt; Darreh-Shori, Taher

2016-08-01

Recent reports have brought back the acetylcholine synthesizing enzyme, choline acetyltransferase in the mainstream research in dementia and the cholinergic anti-inflammatory pathway. Here we report, a specific strategy for the design of novel ChAT ligands based on molecular docking, Hologram Quantitative Structure Activity Relationship (HQSAR) and lead optimization. Molecular docking was performed on a series of ChAT inhibitors to decipher the molecular fingerprint of their interaction with the active site of ChAT. Then robust statistical fragment HQSAR models were developed. A library of novel ligands was generated based on the pharmacophoric and shape similarity scoring function, and evaluated in silico for their molecular interactions with ChAT. Ten of the top scoring invented compounds are reported here. We confirmed the activity of α-NETA, the only commercially available ChAT inhibitor, and one of the seed compounds in our model, using a new simple colorimetric ChAT assay (IC50 ~ 88 nM). In contrast, α-NETA exhibited an IC50 of ~30 μM for the ACh-degrading cholinesterases. In conclusion, the overall results may provide useful insight for discovering novel ChAT ligands and potential positron emission tomography tracers as in vivo functional biomarkers of the health of central cholinergic system in neurodegenerative disorders, such as Alzheimer’s disease.

In silico modelling and molecular dynamics simulation studies of thiazolidine based PTP1B inhibitors.

PubMed

Mahapatra, Manoj Kumar; Bera, Krishnendu; Singh, Durg Vijay; Kumar, Rajnish; Kumar, Manoj

2018-04-01

Protein tyrosine phosphatase 1B (PTP1B) has been identified as a negative regulator of insulin and leptin signalling pathway; hence, it can be considered as a new therapeutic target of intervention for the treatment of type 2 diabetes. Inhibition of this molecular target takes care of both diabetes and obesity, i.e. diabestiy. In order to get more information on identification and optimization of lead, pharmacophore modelling, atom-based 3D QSAR, docking and molecular dynamics studies were carried out on a set of ligands containing thiazolidine scaffold. A six-point pharmacophore model consisting of three hydrogen bond acceptor (A), one negative ionic (N) and two aromatic rings (R) with discrete geometries as pharmacophoric features were developed for a predictive 3D QSAR model. The probable binding conformation of the ligands within the active site was studied through molecular docking. The molecular interactions and the structural features responsible for PTP1B inhibition and selectivity were further supplemented by molecular dynamics simulation study for a time scale of 30 ns. The present investigation has identified some of the indispensible structural features of thiazolidine analogues which can further be explored to optimize PTP1B inhibitors.

Coarse gaining of molecular crystals: limitations imposed by molecular flexibility

NASA Astrophysics Data System (ADS)

Picu, Catalin; Pal, Anirban

Molecular crystals include molecular electronics, energetic materials, pharmaceuticals and some food components. In many of these applications the small scale mechanical behavior of the crystal is important such as for example in energetic materials where detonation is induced by the formation of hot spots which are induced thermomechanically, and in pharmaceuticals where phase stability is critical for the biochemical activity of the drug. Accurate modeling of these processes requires resolving the atomistic scale details of the material. However, the cost of these models is very large due to the complexity of the molecules forming the crystal, and some form of coarse graning is necessary. In this study we identify the limitations imposed by the need to accurately capture molecular flexibility on the development of coarse grained models for the energetic molecular crystal RDX. We define guidelines for the definition of coarse grained models that target elastic and plastic crystal scale properties such as elastic constants, thermal expansion, compressibility, the critical stress for the motion of dislocations (Peierls stress) and the stacking fault energy This work was supported by the ARO through Grant W911NF-09-1-0330 and AFRL through Grant FA8651-16-1-0004.

Integrated machine learning, molecular docking and 3D-QSAR based approach for identification of potential inhibitors of trypanosomal N-myristoyltransferase.

PubMed

Singh, Nidhi; Shah, Priyanka; Dwivedi, Hemlata; Mishra, Shikha; Tripathi, Renu; Sahasrabuddhe, Amogh A; Siddiqi, Mohammad Imran

2016-11-15

N-Myristoyltransferase (NMT) catalyzes the transfer of myristate to the amino-terminal glycine of a subset of proteins, a co-translational modification involved in trafficking substrate proteins to membrane locations, stabilization and protein-protein interactions. It is a studied and validated pre-clinical drug target for fungal and parasitic infections. In the present study, a machine learning approach, docking studies and CoMFA analysis have been integrated with the objective of translation of knowledge into a pipelined workflow towards the identification of putative hits through the screening of large compound libraries. In the proposed pipeline, the reported parasitic NMT inhibitors have been used to develop predictive machine learning classification models. Simultaneously, a TbNMT complex model was generated to establish the relationship between the binding mode of the inhibitors for LmNMT and TbNMT through molecular dynamics simulation studies. A 3D-QSAR model was developed and used to predict the activity of the proposed hits in the subsequent step. The hits classified as active based on the machine learning model were assessed as the potential anti-trypanosomal NMT inhibitors through molecular docking studies, predicted activity using a QSAR model and visual inspection. In the final step, the proposed pipeline was validated through in vitro experiments. A total of seven hits have been proposed and tested in vitro for evaluation of dual inhibitory activity against Leishmania donovani and Trypanosoma brucei. Out of these five compounds showed significant inhibition against both of the organisms. The common topmost active compound SEW04173 belongs to a pyrazole carboxylate scaffold and is anticipated to enrich the chemical space with enhanced potency through optimization.

Integrating a Smartphone and Molecular Modeling for Determining the Binding Constant and Stoichiometry Ratio of the Iron(II)-Phenanthroline Complex: An Activity for Analytical and Physical Chemistry Laboratories

ERIC Educational Resources Information Center

de Morais, Camilo de L. M.; Silva, Se´rgio R. B.; Vieira, Davi S.; Lima, Ka´ssio M. G.

2016-01-01

The binding constant and stoichiometry ratio for the formation of iron(II)-(1,10-phenanthroline) or iron(II)-o-phenanthroline complexes has been determined by a combination of a low-cost analytical method using a smartphone and a molecular modeling method as a laboratory experiment designed for analytical and physical chemistry courses. Intensity…

Tuning complement activation and pathway through controlled molecular architecture of dextran chains in nanoparticle corona.

PubMed

Coty, Jean-Baptiste; Eleamen Oliveira, Elquio; Vauthier, Christine

2017-11-05

The understanding of complement activation by nanomaterials is a key to a rational design of safe and efficient nanomedicines. This work proposed a systematic study investigating how molecular design of nanoparticle coronas made of dextran impacts on mechanisms that trigger complement activation. The nanoparticles used for this work consisted of dextran-coated poly(isobutylcyanoacrylate) (PIBCA) nanoparticles have already been thoroughly characterized. Their different capacity to trigger complement activation established on the cleavage of the protein C3 was also already described making these nanoparticles good models to investigate the relation between the molecular feature of their corona and the mechanism by which they triggered complement activation. Results of this new study show that complement activation pathways can be selected by distinct architectures formed by dextran chains composing the nanoparticle corona. Assumptions that explain the relation between complement activation mechanisms triggered by the nanoparticles and the nanoparticle corona molecular feature were proposed. These results are of interest to better understand how the design of dextran-coated nanomaterials will impact interactions with the complement system. It can open perspectives with regard to the selection of a preferential complement activation pathway or prevent the nanoparticles to activate the complement system, based on a rational choice of the corona configuration. Copyright © 2017 Elsevier B.V. All rights reserved.

Discovery of an Unexplored Protein Structural Scaffold of Serine Protease from Big Blue Octopus (Octopus cyanea): A New Prospective Lead Molecule.

PubMed

Panda, Subhamay; Kumari, Leena

2017-01-01

Serine proteases are a group of enzymes that hydrolyses the peptide bonds in proteins. In mammals, these enzymes help in the regulation of several major physiological functions such as digestion, blood clotting, responses of immune system, reproductive functions and the complement system. Serine proteases obtained from the venom of Octopodidae family is a relatively unexplored area of research. In the present work, we tried to effectively utilize comparative composite molecular modeling technique. Our key aim was to propose the first molecular model structure of unexplored serine protease 5 derived from big blue octopus. The other objective of this study was to analyze the distribution of negatively and positively charged amino acid over molecular modeled structure, distribution of secondary structural elements, hydrophobicity molecular surface analysis and electrostatic potential analysis with the aid of different bioinformatic tools. In the present study, molecular model has been generated with the help of I-TASSER suite. Afterwards the refined structural model was validated with standard methods. For functional annotation of protein molecule we used Protein Information Resource (PIR) database. Serine protease 5 of big blue octopus was analyzed with different bioinformatical algorithms for the distribution of negatively and positively charged amino acid over molecular modeled structure, distribution of secondary structural elements, hydrophobicity molecular surface analysis and electrostatic potential analysis. The functionally critical amino acids and ligand- binding site (LBS) of the proteins (modeled) were determined using the COACH program. The molecular model data in cooperation to other pertinent post model analysis data put forward molecular insight to proteolytic activity of serine protease 5, which helps in the clear understanding of procoagulant and anticoagulant characteristics of this natural lead molecule. Our approach was to investigate the octopus venom protein as a whole or a part of their structure that may result in the development of new lead molecule. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Activities of mixtures of soil-applied herbicides with different molecular targets.

PubMed

Kaushik, Shalini; Streibig, Jens Carl; Cedergreen, Nina

2006-11-01

The joint action of soil-applied herbicide mixtures with similar or different modes of action has been assessed by using the additive dose model (ADM). The herbicides chlorsulfuron, metsulfuron-methyl, pendimethalin and pretilachlor, applied either singly or in binary mixtures, were used on rice (Oryza sativa L.). The growth (shoot) response curves were described by a logistic dose-response model. The ED50 values and their corresponding standard errors obtained from the response curves were used to test statistically if the shape of the isoboles differed from the reference model (ADM). Results showed that mixtures of herbicides with similar molecular targets, i.e. chlorsulfuron and metsulfuron (acetolactate synthase (ALS) inhibitors), and with different molecular targets, i.e. pendimethalin (microtubule assembly inhibitor) and pretilachlor (very long chain fatty acids (VLCFAs) inhibitor), followed the ADM. Mixing herbicides with different molecular targets gave different results depending on whether pretilachlor or pendimethalin was involved. In general, mixtures of pretilachlor and sulfonylureas showed synergistic interactions, whereas mixtures of pendimethalin and sulfonylureas exhibited either antagonistic or additive activities. Hence, there is a large potential for both increasing the specificity of herbicides by using mixtures and lowering the total dose for weed control, while at the same time delaying the development of herbicide resistance by using mixtures with different molecular targets. Copyright (c) 2006 Society of Chemical Industry.

Insight into the structural requirements of proton pump inhibitors based on CoMFA and CoMSIA studies.

PubMed

Nayana, M Ravi Shashi; Sekhar, Y Nataraja; Nandyala, Haritha; Muttineni, Ravikumar; Bairy, Santosh Kumar; Singh, Kriti; Mahmood, S K

2008-10-01

In the present study, a series of 179 quinoline and quinazoline heterocyclic analogues exhibiting inhibitory activity against Gastric (H+/K+)-ATPase were investigated using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA) methods. Both the models exhibited good correlation between the calculated 3D-QSAR fields and the observed biological activity for the respective training set compounds. The most optimal CoMFA and CoMSIA models yielded significant leave-one-out cross-validation coefficient, q(2) of 0.777, 0.744 and conventional cross-validation coefficient, r(2) of 0.927, 0.914 respectively. The predictive ability of generated models was tested on a set of 52 compounds having broad range of activity. CoMFA and CoMSIA yielded predicted activities for test set compounds with r(pred)(2) of 0.893 and 0.917 respectively. These validation tests not only revealed the robustness of the models but also demonstrated that for our models r(pred)(2) based on the mean activity of test set compounds can accurately estimate external predictivity. The factors affecting activity were analyzed carefully according to standard coefficient contour maps of steric, electrostatic, hydrophobic, acceptor and donor fields derived from the CoMFA and CoMSIA. These contour plots identified several key features which explain the wide range of activities. The results obtained from models offer important structural insight into designing novel peptic-ulcer inhibitors prior to their synthesis.

Combined molecular docking, molecular dynamics simulation and quantitative structure-activity relationship study of pyrimido[1,2-c][1,3]benzothiazin-6-imine derivatives as potent anti-HIV drugs

NASA Astrophysics Data System (ADS)

Deng, Fangfang; Xie, Meihong; Zhang, Xiaoyun; Li, Peizhen; Tian, Yueli; Zhai, Honglin; Li, Yang

2014-06-01

3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine is an antiretroviral agent, which can act against human immunodeficiency virus (HIV) infection, but the mechanism of action of pyrimido[1,2-c][1,3]benzothiazin-6-imine derivatives remained ambiguous. In this study, multiple linear regression (MLR) was applied to establish a quite reliable model with the squared correlation coefficient (R2) of 0.8079. We also used chemical information descriptors based on the simplified molecular input line entry system (SMILES) to get a better model with R2 of 0.9086 for the training set, and R2 of 0.8031 for the test set. Molecular docking was utilized to provide more useful information between pyrimido[1,2-c][1,3]benzothiazin-6-imine derivatives and HIV-1 protease, such as active site, binding mode and important residues. Molecular dynamics simulation was employed to further validate the docking results. This work may lead to a better understanding of the mechanism of action and aid to design novel and more potent anti-HIV drugs.

In Silico Exploration of 1,7-Diazacarbazole Analogs as Checkpoint Kinase 1 Inhibitors by Using 3D QSAR, Molecular Docking Study, and Molecular Dynamics Simulations.

PubMed

Gao, Xiaodong; Han, Liping; Ren, Yujie

2016-05-05

Checkpoint kinase 1 (Chk1) is an important serine/threonine kinase with a self-protection function. The combination of Chk1 inhibitors and anti-cancer drugs can enhance the selectivity of tumor therapy. In this work, a set of 1,7-diazacarbazole analogs were identified as potent Chk1 inhibitors through a series of computer-aided drug design processes, including three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling, molecular docking, and molecular dynamics simulations. The optimal QSAR models showed significant cross-validated correlation q² values (0.531, 0.726), fitted correlation r² coefficients (higher than 0.90), and standard error of prediction (less than 0.250). These results suggested that the developed models possess good predictive ability. Moreover, molecular docking and molecular dynamics simulations were applied to highlight the important interactions between the ligand and the Chk1 receptor protein. This study shows that hydrogen bonding and electrostatic forces are key interactions that confer bioactivity.

3D-QSAR and docking studies of flavonoids as potent Escherichia coli inhibitors

PubMed Central

Fang, Yajing; Lu, Yulin; Zang, Xixi; Wu, Ting; Qi, XiaoJuan; Pan, Siyi; Xu, Xiaoyun

2016-01-01

Flavonoids are potential antibacterial agents. However, key substituents and mechanism for their antibacterial activity have not been fully investigated. The quantitative structure-activity relationship (QSAR) and molecular docking of flavonoids relating to potent anti-Escherichia coli agents were investigated. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were developed by using the pIC50 values of flavonoids. The cross-validated coefficient (q2) values for CoMFA (0.743) and for CoMSIA (0.708) were achieved, illustrating high predictive capabilities. Selected descriptors for the CoMFA model were ClogP (logarithm of the octanol/water partition coefficient), steric and electrostatic fields, while, ClogP, electrostatic and hydrogen bond donor fields were used for the CoMSIA model. Molecular docking results confirmed that half of the tested flavonoids inhibited DNA gyrase B (GyrB) by interacting with adenosine-triphosphate (ATP) pocket in a same orientation. Polymethoxyl flavones, flavonoid glycosides, isoflavonoids changed their orientation, resulting in a decrease of inhibitory activity. Moreover, docking results showed that 3-hydroxyl, 5-hydroxyl, 7-hydroxyl and 4-carbonyl groups were found to be crucial active substituents of flavonoids by interacting with key residues of GyrB, which were in agreement with the QSAR study results. These results provide valuable information for structure requirements of flavonoids as antibacterial agents. PMID:27049530

Quantitative structure activity relationship (QSAR) of piperine analogs for bacterial NorA efflux pump inhibitors.

PubMed

Nargotra, Amit; Sharma, Sujata; Koul, Jawahir Lal; Sangwan, Pyare Lal; Khan, Inshad Ali; Kumar, Ashwani; Taneja, Subhash Chander; Koul, Surrinder

2009-10-01

Quantitative structure activity relationship (QSAR) analysis of piperine analogs as inhibitors of efflux pump NorA from Staphylococcus aureus has been performed in order to obtain a highly accurate model enabling prediction of inhibition of S. aureus NorA of new chemical entities from natural sources as well as synthetic ones. Algorithm based on genetic function approximation method of variable selection in Cerius2 was used to generate the model. Among several types of descriptors viz., topological, spatial, thermodynamic, information content and E-state indices that were considered in generating the QSAR model, three descriptors such as partial negative surface area of the compounds, area of the molecular shadow in the XZ plane and heat of formation of the molecules resulted in a statistically significant model with r(2)=0.962 and cross-validation parameter q(2)=0.917. The validation of the QSAR models was done by cross-validation, leave-25%-out and external test set prediction. The theoretical approach indicates that the increase in the exposed partial negative surface area increases the inhibitory activity of the compound against NorA whereas the area of the molecular shadow in the XZ plane is inversely proportional to the inhibitory activity. This model also explains the relationship of the heat of formation of the compound with the inhibitory activity. The model is not only able to predict the activity of new compounds but also explains the important regions in the molecules in quantitative manner.

A Model for the Epigenetic Switch Linking Inflammation to Cell Transformation: Deterministic and Stochastic Approaches

PubMed Central

Gérard, Claude; Gonze, Didier; Lemaigre, Frédéric; Novák, Béla

2014-01-01

Recently, a molecular pathway linking inflammation to cell transformation has been discovered. This molecular pathway rests on a positive inflammatory feedback loop between NF-κB, Lin28, Let-7 microRNA and IL6, which leads to an epigenetic switch allowing cell transformation. A transient activation of an inflammatory signal, mediated by the oncoprotein Src, activates NF-κB, which elicits the expression of Lin28. Lin28 decreases the expression of Let-7 microRNA, which results in higher level of IL6 than achieved directly by NF-κB. In turn, IL6 can promote NF-κB activation. Finally, IL6 also elicits the synthesis of STAT3, which is a crucial activator for cell transformation. Here, we propose a computational model to account for the dynamical behavior of this positive inflammatory feedback loop. By means of a deterministic model, we show that an irreversible bistable switch between a transformed and a non-transformed state of the cell is at the core of the dynamical behavior of the positive feedback loop linking inflammation to cell transformation. The model indicates that inhibitors (tumor suppressors) or activators (oncogenes) of this positive feedback loop regulate the occurrence of the epigenetic switch by modulating the threshold of inflammatory signal (Src) needed to promote cell transformation. Both stochastic simulations and deterministic simulations of a heterogeneous cell population suggest that random fluctuations (due to molecular noise or cell-to-cell variability) are able to trigger cell transformation. Moreover, the model predicts that oncogenes/tumor suppressors respectively decrease/increase the robustness of the non-transformed state of the cell towards random fluctuations. Finally, the model accounts for the potential effect of competing endogenous RNAs, ceRNAs, on the dynamics of the epigenetic switch. Depending on their microRNA targets, the model predicts that ceRNAs could act as oncogenes or tumor suppressors by regulating the occurrence of cell transformation. PMID:24499937

Water activity and mobility in solutions of glycerol and small molecular weight sugars: Implication for cryo- and lyopreservation

NASA Astrophysics Data System (ADS)

He, Xiaoming; Fowler, Alex; Toner, Mehmet

2006-10-01

In this study, the free volume models, originally developed for large molecular weight polymer-solvent systems, were used to study the water activity and mobility in solutions of four small molecular weight cryo-/lyoprotectants, viz., glycerol, a monosaccharide (fructose), and two disaccharides (sucrose and trehalose). The free volume model parameters were determined by fitting the models to available experimental data using a nonlinear optimization procedure. It was found that free volume models could accurately predict the available experimental data, which suggests that the free volume models might be generally applicable to aqueous solutions of small molecular weight cryo-/lyoprotectants. Furthermore, several models for estimating the mutual diffusion coefficient were tested using available experimental data for aqueous solutions of glycerol and a better method to estimate the mutual diffusion coefficient was proposed. Free volume models were used to predict and analyze the water activity and mobility in solutions of four cryo-/lyoprotectants under conditions frequently encountered in cryo-/lyopreservation applications. It was found that the water mobility in the glassy state of the above four solutions is essentially negligible in the case of cryopreservation with storage temperature lower than -110°C. However, the water mobility in a glass at higher temperature (>-80°C) may be significant. As a result, a subcooling of up to 50°C may be necessary for the long-term cryo-/lyopreservation of biomaterials depending on the water content and the type of cryo-/lyoprotectants. It was further shown that trehalose might be the best of the four protectants studied for lyopreservation (water mass fraction ⩽0.1) when the storage temperature is above the room temperature. The results from this study might be useful for the development of more effective protocols for both cryopreservation and lyopreservation of living cells and other biomaterials.

Application of 3D-QSAR, Pharmacophore, and Molecular Docking in the Molecular Design of Diarylpyrimidine Derivatives as HIV-1 Nonnucleoside Reverse Transcriptase Inhibitors.

PubMed

Liu, Genyan; Wang, Wenjie; Wan, Youlan; Ju, Xiulian; Gu, Shuangxi

2018-05-11

Diarylpyrimidines (DAPYs), acting as HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs), have been considered to be one of the most potent drug families in the fight against acquired immunodeficiency syndrome (AIDS). To better understand the structural requirements of HIV-1 NNRTIs, three-dimensional quantitative structure⁻activity relationship (3D-QSAR), pharmacophore, and molecular docking studies were performed on 52 DAPY analogues that were synthesized in our previous studies. The internal and external validation parameters indicated that the generated 3D-QSAR models, including comparative molecular field analysis (CoMFA, q 2 = 0.679, R 2 = 0.983, and r pred 2 = 0.884) and comparative molecular similarity indices analysis (CoMSIA, q 2 = 0.734, R 2 = 0.985, and r pred 2 = 0.891), exhibited good predictive abilities and significant statistical reliability. The docking results demonstrated that the phenyl ring at the C₄-position of the pyrimidine ring was better than the cycloalkanes for the activity, as the phenyl group was able to participate in π⁻π stacking interactions with the aromatic residues of the binding site, whereas the cycloalkanes were not. The pharmacophore model and 3D-QSAR contour maps provided significant insights into the key structural features of DAPYs that were responsible for the activity. On the basis of the obtained information, a series of novel DAPY analogues of HIV-1 NNRTIs with potentially higher predicted activity was designed. This work might provide useful information for guiding the rational design of potential HIV-1 NNRTI DAPYs.

Selection of molecular descriptors with artificial intelligence for the understanding of HIV-1 protease peptidomimetic inhibitors-activity.

PubMed

Sirois, S; Tsoukas, C M; Chou, Kuo-Chen; Wei, Dongqing; Boucher, C; Hatzakis, G E

2005-03-01

Quantitative Structure Activity Relationship (QSAR) techniques are used routinely by computational chemists in drug discovery and development to analyze datasets of compounds. Quantitative numerical methods like Partial Least Squares (PLS) and Artificial Neural Networks (ANN) have been used on QSAR to establish correlations between molecular properties and bioactivity. However, ANN may be advantageous over PLS because it considers the interrelations of the modeled variables. This study focused on the HIV-1 Protease (HIV-1 Pr) inhibitors belonging to the peptidomimetic class of compounds. The main objective was to select molecular descriptors with the best predictive value for antiviral potency (Ki). PLS and ANN were used to predict Ki activity of HIV-1 Pr inhibitors and the results were compared. To address the issue of dimensionality reduction, Genetic Algorithms (GA) were used for variable selection and their performance was compared against that of ANN. Finally, the structure of the optimum ANN achieving the highest Pearson's-R coefficient was determined. On the basis of Pearson's-R, PLS and ANN were compared to determine which exhibits maximum performance. Training and validation of models was performed on 15 random split sets of the master dataset consisted of 231 compounds. For each compound 192 molecular descriptors were considered. The molecular structure and constant of inhibition (Ki) were selected from the NIAID database. Study findings suggested that non-covalent interactions such as hydrophobicity, shape and hydrogen bonding describe well the antiviral activity of the HIV-1 Pr compounds. The significance of lipophilicity and relationship to HIV-1 associated hyperlipidemia and lipodystrophy syndrome warrant further investigation.

The role of the Hippo pathway in human disease and tumorigenesis

PubMed Central

2014-01-01

Understanding the molecular nature of human cancer is essential to the development of effective and personalized therapies. Several different molecular signal transduction pathways drive tumorigenesis when deregulated and respond to different types of therapeutic interventions. The Hippo signaling pathway has been demonstrated to play a central role in the regulation of tissue and organ size during development. The deregulation of Hippo signaling leads to a concurrent combination of uncontrolled cellular proliferation and inhibition of apoptosis, two key hallmarks in cancer development. The molecular nature of this pathway was first uncovered in Drosophila melanogaster through genetic screens to identify regulators of cell growth and cell division. The pathway is strongly conserved in humans, rendering Drosophila a suitable and efficient model system to better understand the molecular nature of this pathway. In the present study, we review the current understanding of the molecular mechanism and clinical impact of the Hippo pathway. Current studies have demonstrated that a variety of deregulated molecules can alter Hippo signaling, leading to the constitutive activation of the transcriptional activator YAP or its paralog TAZ. Additionally, the Hippo pathway integrates inputs from a number of growth signaling pathways, positioning the Hippo pathway in a central role in the regulation of tissue size. Importantly, deregulated Hippo signaling is frequently observed in human cancers. YAP is commonly activated in a number of in vitro and in vivo models of tumorigenesis, as well as a number of human cancers. The common activation of YAP in many different tumor types provides an attractive target for potential therapeutic intervention. PMID:25097728

Combined HQSAR, topomer CoMFA, homology modeling and docking studies on triazole derivatives as SGLT2 inhibitors.

PubMed

Yu, Shuling; Yuan, Jintao; Zhang, Yi; Gao, Shufang; Gan, Ying; Han, Meng; Chen, Yuewen; Zhou, Qiaoqiao; Shi, Jiahua

2017-06-01

Sodium-glucose cotransporter 2 (SGLT2) is a promising target for diabetes therapy. We aimed to develop computational approaches to identify structural features for more potential SGLT2 inhibitors. In this work, 46 triazole derivatives as SGLT2 inhibitors were studied using a combination of several approaches, including hologram quantitative structure-activity relationships (HQSAR), topomer comparative molecular field analysis (CoMFA), homology modeling, and molecular docking. HQSAR and topomer CoMFA were used to construct models. Molecular docking was conducted to investigate the interaction of triazole derivatives and homology modeling of SGLT2, as well as to validate the results of the HQSAR and topomer CoMFA models. The most effective HQSAR and topomer CoMFA models exhibited noncross-validated correlation coefficients of 0.928 and 0.891 for the training set, respectively. External predictions were made successfully on a test set and then compared with previously reported models. The graphical results of HQSAR and topomer CoMFA were proven to be consistent with the binding mode of the inhibitors and SGLT2 from molecular docking. The models and docking provided important insights into the design of potent inhibitors for SGLT2.

A Model of How Different Biology Experts Explain Molecular and Cellular Mechanisms

PubMed Central

Trujillo, Caleb M.; Anderson, Trevor R.; Pelaez, Nancy J.

2015-01-01

Constructing explanations is an essential skill for all science learners. The goal of this project was to model the key components of expert explanation of molecular and cellular mechanisms. As such, we asked: What is an appropriate model of the components of explanation used by biology experts to explain molecular and cellular mechanisms? Do explanations made by experts from different biology subdisciplines at a university support the validity of this model? Guided by the modeling framework of R. S. Justi and J. K. Gilbert, the validity of an initial model was tested by asking seven biologists to explain a molecular mechanism of their choice. Data were collected from interviews, artifacts, and drawings, and then subjected to thematic analysis. We found that biologists explained the specific activities and organization of entities of the mechanism. In addition, they contextualized explanations according to their biological and social significance; integrated explanations with methods, instruments, and measurements; and used analogies and narrated stories. The derived methods, analogies, context, and how themes informed the development of our final MACH model of mechanistic explanations. Future research will test the potential of the MACH model as a guiding framework for instruction to enhance the quality of student explanations. PMID:25999313

Stochastic dynamics of coupled active particles in an overdamped limit

NASA Astrophysics Data System (ADS)

Ann, Minjung; Lee, Kong-Ju-Bock; Park, Pyeong Jun

2015-10-01

We introduce a model for Brownian dynamics of coupled active particles in an overdamped limit. Our system consists of several identical active particles and one passive particle. Each active particle is elastically coupled to the passive particle and there is no direct coupling among the active particles. We investigate the dynamics of the system with respect to the number of active particles, viscous friction, and coupling between the active and passive particles. For this purpose, we consider an intracellular transport process as an application of our model and perform a Brownian dynamics simulation using realistic parameters for processive molecular motors such as kinesin-1. We determine an adequate energy conversion function for molecular motors and study the dynamics of intracellular transport by multiple motors. The results show that the average velocity of the coupled system is not affected by the number of active motors and that the stall force increases linearly as the number of motors increases. Our results are consistent with well-known experimental observations. We also examine the effects of coupling between the motors and the cargo, as well as of the spatial distribution of the motors around the cargo. Our model might provide a physical explanation of the cooperation among active motors in the cellular transport processes.

QSAR studies on triazole derivatives as sglt inhibitors via CoMFA and CoMSIA

NASA Astrophysics Data System (ADS)

Zhi, Hui; Zheng, Junxia; Chang, Yiqun; Li, Qingguo; Liao, Guochao; Wang, Qi; Sun, Pinghua

2015-10-01

Forty-six sodium-dependent glucose cotransporters-2 (SGLT-2) inhibitors with hypoglycemic activity were selected to develop three-dimensional quantitative structure-activity relationship (3D-QSAR) using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models. A training set of 39 compounds were used to build up the models, which were then evaluated by a series of internal and external cross-validation techniques. A test set of 7 compounds was used for the external validation. The CoMFA model predicted a q2 value of 0.792 and an r2 value of 0.985. The best CoMSIA model predicted a q2 value of 0.633 and an r2 value of 0.895 based on a combination of steric, electrostatic, hydrophobic and hydrogen-bond acceptor effects. The predictive correlation coefficients (rpred2) of CoMFA and CoMSIA models were 0.872 and 0.839, respectively. The analysis of the contour maps from each model provided insight into the structural requirements for the development of more active sglt inhibitors, and on the basis of the models 8 new sglt inhibitors were designed and predicted.

Multiple biological activities and molecular docking studies of newly synthesized 3-(pyridin-4-yl)-1H-pyrazole-5-carboxamide chalcone hybrids.

PubMed

Sribalan, Rajendran; Banuppriya, Govindharasu; Kirubavathi, Maruthan; Jayachitra, A; Padmini, Vediappen

2016-12-01

A series of fifteen new chemical entities, 3-(pyridin-4-yl)-1H-pyrazole-5-carboxamide chalcones (6a-o), were synthesized as new hybrids with enriched biological activities compared to their parent molecules. The compounds were characterized by 1 H NMR, 13 C NMR, Mass and IR spectral studies. Their antibacterial, anti-inflammatory and antioxidant activities have been evaluated. These compounds showed moderate to good antibacterial, anti-inflammatory and antioxidant activities. The molecular docking analysis was performed with cyclooxygenase enzyme to ascertain the probable binding model. Copyright © 2016 Elsevier Ltd. All rights reserved.

Automated building of organometallic complexes from 3D fragments.

PubMed

Foscato, Marco; Venkatraman, Vishwesh; Occhipinti, Giovanni; Alsberg, Bjørn K; Jensen, Vidar R

2014-07-28

A method for the automated construction of three-dimensional (3D) molecular models of organometallic species in design studies is described. Molecular structure fragments derived from crystallographic structures and accurate molecular-level calculations are used as 3D building blocks in the construction of multiple molecular models of analogous compounds. The method allows for precise control of stereochemistry and geometrical features that may otherwise be very challenging, or even impossible, to achieve with commonly available generators of 3D chemical structures. The new method was tested in the construction of three sets of active or metastable organometallic species of catalytic reactions in the homogeneous phase. The performance of the method was compared with those of commonly available methods for automated generation of 3D models, demonstrating higher accuracy of the prepared 3D models in general, and, in particular, a much wider range with respect to the kind of chemical structures that can be built automatically, with capabilities far beyond standard organic and main-group chemistry.

Recent insights into the molecular mechanisms of the NLRP3 inflammasome activation

PubMed Central

Próchnicki, Tomasz; Mangan, Matthew S.; Latz, Eicke

2016-01-01

Inflammasomes are high-molecular-weight protein complexes that are formed in the cytosolic compartment in response to danger- or pathogen-associated molecular patterns. These complexes enable activation of an inflammatory protease caspase-1, leading to a cell death process called pyroptosis and to proteolytic cleavage and release of pro-inflammatory cytokines interleukin (IL)-1β and IL-18. Along with caspase-1, inflammasome components include an adaptor protein, ASC, and a sensor protein, which triggers the inflammasome assembly in response to a danger signal. The inflammasome sensor proteins are pattern recognition receptors belonging either to the NOD-like receptor (NLR) or to the AIM2-like receptor family. While the molecular agonists that induce inflammasome formation by AIM2 and by several other NLRs have been identified, it is not well understood how the NLR family member NLRP3 is activated. Given that NLRP3 activation is relevant to a range of human pathological conditions, significant attempts are being made to elucidate the molecular mechanism of this process. In this review, we summarize the current knowledge on the molecular events that lead to activation of the NLRP3 inflammasome in response to a range of K + efflux-inducing danger signals. We also comment on the reported involvement of cytosolic Ca 2+ fluxes on NLRP3 activation. We outline the recent advances in research on the physiological and pharmacological mechanisms of regulation of NLRP3 responses, and we point to several open questions regarding the current model of NLRP3 activation. PMID:27508077

Pickpocket1 Is an Ionotropic Molecular Sensory Transducer*

PubMed Central

Boiko, Nina; Kucher, Volodymyr; Stockand, James D.; Eaton, Benjamin A.

2012-01-01

The molecular transformation of an external stimulus into changes in sensory neuron activity is incompletely described. Although a number of molecules have been identified that can respond to stimuli, evidence that these molecules can transduce stimulation into useful neural activity is lacking. Here we demonstrate that pickpocket1 (ppk1), a Drosophila homolog of mammalian Degenerin/epithelial sodium channels, encodes an acid-sensing sodium channel that conducts a transient depolarizing current in multidendritic sensory neurons of Drosophila melanogaster. Stimulation of Ppk1 is sufficient to bring these sensory neurons to threshold, eliciting a burst of action potentials. The transient nature of the neural activity produced by Ppk1 activation is the result of Ppk1 channel gating properties. This model is supported by the observation of enhanced bursting activity in neurons expressing a gain of function ppk1 mutant harboring the degenerin mutation. These findings demonstrate that Ppk1 can function as an ionotropic molecular sensory transducer capable of transforming the perception of a stimulus into phasic neuronal activity in sensory neurons. PMID:23033486

Inactive and active states and supramolecular organization of GPCRs: insights from computational modeling

NASA Astrophysics Data System (ADS)

Fanelli, Francesca; De Benedetti, Pier G.

2006-08-01

Herein we make an overview of the results of our computational experiments aimed at gaining insight into the molecular mechanisms of GPCR functioning either in their normal conditions or when hit by gain-of-function or loss-of-function mutations. Molecular simulations of a number of GPCRs in their wild type and mutated as well as free and ligand-bound forms were instrumental in inferring the structural features, which differentiate the mutation- and ligand-induced active from the inactive states. These features essentially reside in the interaction pattern of the E/DRY arginine and in the degree of solvent exposure of selected cytosolic domains. Indeed, the active states differ from the inactive ones in the weakening of the interactions made by the highly conserved arginine and in the increase in solvent accessibility of the cytosolic interface between helices 3 and 6. Where possible, the structural hallmarks of the active and inactive receptor states are translated into molecular descriptors useful for in silico functional screening of novel receptor mutants or ligands. Computational modeling of the supramolecular organization of GPCRs and their intracellular partners is the current challenge toward a deep understanding of their functioning mechanisms.

Quantum chemical and statistical study of megazol-derived compounds with trypanocidal activity

NASA Astrophysics Data System (ADS)

Rosselli, F. P.; Albuquerque, C. N.; da Silva, A. B. F.

In this work we performed a structure-activity relationship (SAR) study with the aim to correlate molecular properties of the megazol compound and 10 of its analogs with the biological activity against Trypanosoma cruzi (trypanocidal or antichagasic activity) presented by these molecules. The biological activity indication was obtained from in vitro tests and the molecular properties (variables or descriptors) were obtained from the optimized chemical structures by using the PM3 semiempirical method. It was calculated ˜80 molecular properties selected among steric, constitutional, electronic, and lipophilicity properties. In order to reduce dimensionality and investigate which subset of variables (descriptors) would be more effective in classifying the compounds studied, according to their degree of trypanocidal activity, we employed statistical methodologies (pattern recognition and classification techniques) such as principal component analysis (PCA), hierarchical cluster analysis (HCA), K-nearest neighbor (KNN), and discriminant function analysis (DFA). These methods showed that the descriptors molecular mass (MM), energy of the second lowest unoccupied molecular orbital (LUMO+1), charge on the first nitrogen at substituent 2 (qN'), dihedral angles (D1 and D2), bond length between atom C4 and its substituent (L4), Moriguchi octanol-partition coefficient (MLogP), and length-to-breadth ratio (L/Bw) were the variables responsible for the separation between active and inactive compounds against T. cruzi. Afterwards, the PCA, KNN, and DFA models built in this work were used to perform trypanocidal activity predictions for eight new megazol analog compounds.

Modeling and Prediction of Drug Dispersability in Polyvinylpyrrolidone-Vinyl Acetate Copolymer Using a Molecular Descriptor.

PubMed

DeBoyace, Kevin; Buckner, Ira S; Gong, Yuchuan; Ju, Tzu-Chi Rob; Wildfong, Peter L D

2018-01-01

The expansion of a novel in silico model for the prediction of the dispersability of 18 model compounds with polyvinylpyrrolidone-vinyl acetate copolymer is described. The molecular descriptor R3m (atomic mass weighted 3rd-order autocorrelation index) is shown to be predictive of the formation of amorphous solid dispersions at 2 drug loadings (15% and 75% w/w) using 2 preparation methods (melt quenching and solvent evaporation using a rotary evaporator). Cosolidified samples were characterized using a suite of analytical techniques, which included differential scanning calorimetry, powder X-ray diffraction, pair distribution function analysis, polarized light microscopy, and hot stage microscopy. Logistic regression was applied, where appropriate, to model the success and failure of compound dispersability in polyvinylpyrrolidone-vinyl acetate copolymer. R3m had combined prediction accuracy greater than 90% for tested samples. The usefulness of this descriptor appears to be associated with the presence of heavy atoms in the molecular structure of the active pharmaceutical ingredient, and their location with respect to the geometric center of the molecule. Given the higher electronegativity and atomic volume of these types of atoms, it is hypothesized that they may impact the molecular mobility of the active pharmaceutical ingredient, or increase the likelihood of forming nonbonding interactions with the carrier polymer. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Light-induced conformational changes of LOV1 (light oxygen voltage-sensing domain 1) and LOV2 relative to the kinase domain and regulation of kinase activity in Chlamydomonas phototropin.

PubMed

Okajima, Koji; Aihara, Yusuke; Takayama, Yuki; Nakajima, Mihoko; Kashojiya, Sachiko; Hikima, Takaaki; Oroguchi, Tomotaka; Kobayashi, Amane; Sekiguchi, Yuki; Yamamoto, Masaki; Suzuki, Tomomi; Nagatani, Akira; Nakasako, Masayoshi; Tokutomi, Satoru

2014-01-03

Phototropin (phot), a blue light (BL) receptor in plants, has two photoreceptive domains named LOV1 and LOV2 as well as a Ser/Thr kinase domain (KD) and acts as a BL-regulated protein kinase. A LOV domain harbors a flavin mononucleotide that undergoes a cyclic photoreaction upon BL excitation via a signaling state in which the inhibition of the kinase activity by LOV2 is negated. To understand the molecular mechanism underlying the BL-dependent activation of the kinase, the photochemistry, kinase activity, and molecular structure were studied with the phot of Chlamydomonas reinhardtii. Full-length and LOV2-KD samples of C. reinhardtii phot showed cyclic photoreaction characteristics with the activation of LOV- and BL-dependent kinase. Truncation of LOV1 decreased the photosensitivity of the kinase activation, which was well explained by the fact that the signaling state lasted for a shorter period of time compared with that of the phot. Small angle x-ray scattering revealed monomeric forms of the proteins in solution and detected BL-dependent conformational changes, suggesting an extension of the global molecular shapes of both samples. Constructed molecular model of full-length phot based on the small angle x-ray scattering data proved the arrangement of LOV1, LOV2, and KD for the first time that showed a tandem arrangement both in the dark and under BL irradiation. The models suggest that LOV1 alters its position relative to LOV2-KD under BL irradiation. This finding demonstrates that LOV1 may interact with LOV2 and modify the photosensitivity of the kinase activation through alteration of the duration of the signaling state in LOV2.

Supporting Students' Knowledge Transfer in Modeling Activities

ERIC Educational Resources Information Center

Piksööt, Jaanika; Sarapuu, Tago

2014-01-01

This study investigates ways to enhance secondary school students' knowledge transfer in complex science domains by implementing question prompts. Two samples of students applied two web-based models to study molecular genetics--the model of genetic code (n = 258) and translation (n = 245). For each model, the samples were randomly divided into…

Efficient heterologous expression, functional characterization and molecular modeling of annular seabream digestive phospholipase A2.

PubMed

Smichi, Nabil; Othman, Houcemeddine; Achouri, Neila; Noiriel, Alexandre; Triki, Soumaya; Arondel, Vincent; Srairi-Abid, Najet; Abousalham, Abdelkarim; Gargouri, Youssef; Miled, Nabil; Fendri, Ahmed

2018-03-01

Here we report the cDNA cloning of a phospholipase A 2 (PLA 2 ) from five Sparidae species. The deduced amino acid sequences show high similarity with pancreatic PLA 2 . In addition, a phylogenetic tree derived from alignment of various available sequences revealed that Sparidae PLA 2 are closer to avian PLA 2 group IB than to mammals' ones. In order to understand the structure-function relationships of these enzymes, we report here the recombinant expression in E.coli, the refolding and characterization of His-tagged annular seabream PLA 2 (AsPLA 2 ). A single Ni-affinity chromatography step was used to obtain a highly purified recombinant AsPLA 2 with a molecular mass of 15kDa as attested by gel electrophoresis and MALDI-TOF mass spectrometry data. The enzyme has a specific activity of 400U.mg -1 measured on phosphatidylcholine at pH 8.5 and 50°C. The enzyme high thermo-activity and thermo-stability make it a potential candidate in various biological applications. The 3D structure models of these enzymes were compared with structures of phylogenetically related pancreatic PLA 2 . By following these models and utilizing molecular dynamics simulations, the resistance of the AsPLA 2 at high temperatures was explained. Using the monomolecular film technique, AsPLA 2 was found to be active on various phospholipids spread at the air/water interface at a surface pressure between 12 and 25dyncm -1 . Interestingly, this enzyme was shown to be mostly active on dilauroyl-phosphatidylglycerol monolayers and this behavior was confirmed by molecular docking and dynamics simulations analysis. The discovery of a thermo-active new member of Sparidae PLA 2 , provides new insights on structure-activity relationships of fish PLA 2 . Copyright © 2017 Elsevier B.V. All rights reserved.

Developing sensor activity relationships for the JPL electronic nose sensors using molecular modeling and QSAR techniques

NASA Technical Reports Server (NTRS)

Shevade, A. V.; Ryan, M. A.; Homer, M. L.; Jewell, A. D.; Zhou, H.; Manatt, K.; Kisor, A. K.

2005-01-01

We report a Quantitative Structure-Activity Relationships (QSAR) study using Genetic Function Approximations (GFA) to describe the polymer-carbon composite sensor activities in the JPL Electronic Nose, when exposed to chemical vapors at parts-per-million concentration levels.

Imidazole derivatives as angiotensin II AT1 receptor blockers: Benchmarks, drug-like calculations and quantitative structure-activity relationships modeling

NASA Astrophysics Data System (ADS)

Alloui, Mebarka; Belaidi, Salah; Othmani, Hasna; Jaidane, Nejm-Eddine; Hochlaf, Majdi

2018-03-01

We performed benchmark studies on the molecular geometry, electron properties and vibrational analysis of imidazole using semi-empirical, density functional theory and post Hartree-Fock methods. These studies validated the use of AM1 for the treatment of larger systems. Then, we treated the structural, physical and chemical relationships for a series of imidazole derivatives acting as angiotensin II AT1 receptor blockers using AM1. QSAR studies were done for these imidazole derivatives using a combination of various physicochemical descriptors. A multiple linear regression procedure was used to design the relationships between molecular descriptor and the activity of imidazole derivatives. Results validate the derived QSAR model.

Modeling of the phase equilibria of polystyrene in methylcyclohexane with semi-empirical quantum mechanical methods I.

PubMed

Wilczura-Wachnik, Hanna; Jónsdóttir, Svava Osk

2003-04-01

A method for calculating interaction parameters traditionally used in phase-equilibrium computations in low-molecular systems has been extended for the prediction of solvent activities of aromatic polymer solutions (polystyrene+methylcyclohexane). Using ethylbenzene as a model compound for the repeating unit of the polymer, the intermolecular interaction energies between the solvent molecule and the polymer were simulated. The semiempirical quantum chemical method AM1, and a method for sampling relevant internal orientations for a pair of molecules developed previously were used. Interaction energies are determined for three molecular pairs, the solvent and the model molecule, two solvent molecules and two model molecules, and used to calculated UNIQUAC interaction parameters, a(ij) and a(ji). Using these parameters, the solvent activities of the polystyrene 90,000 amu+methylcyclohexane system, and the total vapor pressures of the methylcyclohexane+ethylbenzene system were calculated. The latter system was compared to experimental data, giving qualitative agreement. Figure Solvent activities for the methylcylcohexane(1)+polystyrene(2) system at 316 K. Parameters aij (blue line) obtained with the AM1 method; parameters aij (pink line) from VLE data for the ethylbenzene+methylcyclohexane system. The abscissa is the polymer weight fraction defined as y2(x1)=(1mx1)M2/[x1M1+(1mx1)M2], where x1 is the solvent mole fraction and Mi are the molecular weights of the components.

Modeling the Classic Meselson and Stahl Experiment.

ERIC Educational Resources Information Center

D'Agostino, JoBeth

2001-01-01

Points out the importance of molecular models in biology and chemistry. Presents a laboratory activity on DNA. Uses different colored wax strips to represent "heavy" and "light" DNA, cesium chloride for identification of small density differences, and three different liquids with varying densities to model gradient…

Molecular Modeling of Thermodynamic and Transport Properties for CO 2 and Aqueous Brines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jiang, Hao; Economou, Ioannis G.; Panagiotopoulos, Athanassios Z.

Molecular simulation techniques using classical force-fields occupy the space between ab initio quantum mechanical methods and phenomenological correlations. In particular, Monte Carlo and molecular dynamics algorithms can be used to provide quantitative predictions of thermodynamic and transport properties of fluids relevant for geologic carbon sequestration at conditions for which experimental data are uncertain or not available. These methods can cover time and length scales far exceeding those of quantum chemical methods, while maintaining transferability and predictive power lacking from phenomenological correlations. The accuracy of predictions depends sensitively on the quality of the molecular models used. Many existing fixed-point-charge models formore » water and aqueous mixtures fail to represent accurately these fluid properties, especially when descriptions covering broad ranges of thermodynamic conditions are needed. Recent work on development of accurate models for water, CO 2, and dissolved salts, as well as their mixtures, is summarized in this Account. Polarizable models that can respond to the different dielectric environments in aqueous versus nonaqueous phases are necessary for predictions of properties over extended ranges of temperatures and pressures. Phase compositions and densities, activity coefficients of the dissolved salts, interfacial tensions, viscosities and diffusivities can be obtained in near-quantitative agreement to available experimental data, using relatively modest computational resources. In some cases, for example, for the composition of the CO 2-rich phase in coexistence with an aqueous phase, recent results from molecular simulations have helped discriminate among conflicting experimental data sets. The sensitivity of properties on the quality of the intermolecular interaction model varies significantly. Properties such as the phase compositions or electrolyte activity coefficients are much more sensitive than phase densities, viscosities, or component diffusivities. Strong confinement effects on physical properties in nanoscale media can also be directly obtained from molecular simulations. Future work on molecular modeling for CO 2 and aqueous brines is likely to be focused on more systematic generation of interaction models by utilizing quantum chemical as well as direct experimental measurements. New ion models need to be developed for use with the current generation of polarizable water models, including ion–ion interactions that will allow for accurate description of dense, mixed brines. Methods will need to be devised that go beyond the use of effective potentials for incorporation of quantum effects known to be important for water, and reactive force fields developed that can handle bond creation and breaking in systems with carbonate and silicate minerals. Lastly, another area of potential future work is the integration of molecular simulation methods in multiscale models for the chemical reactions leading to mineral dissolution and flow within the porous media in underground formations.« less

Molecular Modeling of Thermodynamic and Transport Properties for CO2 and Aqueous Brines.

PubMed

Jiang, Hao; Economou, Ioannis G; Panagiotopoulos, Athanassios Z

2017-04-18

Molecular simulation techniques using classical force-fields occupy the space between ab initio quantum mechanical methods and phenomenological correlations. In particular, Monte Carlo and molecular dynamics algorithms can be used to provide quantitative predictions of thermodynamic and transport properties of fluids relevant for geologic carbon sequestration at conditions for which experimental data are uncertain or not available. These methods can cover time and length scales far exceeding those of quantum chemical methods, while maintaining transferability and predictive power lacking from phenomenological correlations. The accuracy of predictions depends sensitively on the quality of the molecular models used. Many existing fixed-point-charge models for water and aqueous mixtures fail to represent accurately these fluid properties, especially when descriptions covering broad ranges of thermodynamic conditions are needed. Recent work on development of accurate models for water, CO 2 , and dissolved salts, as well as their mixtures, is summarized in this Account. Polarizable models that can respond to the different dielectric environments in aqueous versus nonaqueous phases are necessary for predictions of properties over extended ranges of temperatures and pressures. Phase compositions and densities, activity coefficients of the dissolved salts, interfacial tensions, viscosities and diffusivities can be obtained in near-quantitative agreement to available experimental data, using relatively modest computational resources. In some cases, for example, for the composition of the CO 2 -rich phase in coexistence with an aqueous phase, recent results from molecular simulations have helped discriminate among conflicting experimental data sets. The sensitivity of properties on the quality of the intermolecular interaction model varies significantly. Properties such as the phase compositions or electrolyte activity coefficients are much more sensitive than phase densities, viscosities, or component diffusivities. Strong confinement effects on physical properties in nanoscale media can also be directly obtained from molecular simulations. Future work on molecular modeling for CO 2 and aqueous brines is likely to be focused on more systematic generation of interaction models by utilizing quantum chemical as well as direct experimental measurements. New ion models need to be developed for use with the current generation of polarizable water models, including ion-ion interactions that will allow for accurate description of dense, mixed brines. Methods will need to be devised that go beyond the use of effective potentials for incorporation of quantum effects known to be important for water, and reactive force fields developed that can handle bond creation and breaking in systems with carbonate and silicate minerals. Another area of potential future work is the integration of molecular simulation methods in multiscale models for the chemical reactions leading to mineral dissolution and flow within the porous media in underground formations.

Molecular Modeling of Thermodynamic and Transport Properties for CO 2 and Aqueous Brines

DOE PAGES

Jiang, Hao; Economou, Ioannis G.; Panagiotopoulos, Athanassios Z.

2017-02-24

Molecular simulation techniques using classical force-fields occupy the space between ab initio quantum mechanical methods and phenomenological correlations. In particular, Monte Carlo and molecular dynamics algorithms can be used to provide quantitative predictions of thermodynamic and transport properties of fluids relevant for geologic carbon sequestration at conditions for which experimental data are uncertain or not available. These methods can cover time and length scales far exceeding those of quantum chemical methods, while maintaining transferability and predictive power lacking from phenomenological correlations. The accuracy of predictions depends sensitively on the quality of the molecular models used. Many existing fixed-point-charge models formore » water and aqueous mixtures fail to represent accurately these fluid properties, especially when descriptions covering broad ranges of thermodynamic conditions are needed. Recent work on development of accurate models for water, CO 2, and dissolved salts, as well as their mixtures, is summarized in this Account. Polarizable models that can respond to the different dielectric environments in aqueous versus nonaqueous phases are necessary for predictions of properties over extended ranges of temperatures and pressures. Phase compositions and densities, activity coefficients of the dissolved salts, interfacial tensions, viscosities and diffusivities can be obtained in near-quantitative agreement to available experimental data, using relatively modest computational resources. In some cases, for example, for the composition of the CO 2-rich phase in coexistence with an aqueous phase, recent results from molecular simulations have helped discriminate among conflicting experimental data sets. The sensitivity of properties on the quality of the intermolecular interaction model varies significantly. Properties such as the phase compositions or electrolyte activity coefficients are much more sensitive than phase densities, viscosities, or component diffusivities. Strong confinement effects on physical properties in nanoscale media can also be directly obtained from molecular simulations. Future work on molecular modeling for CO 2 and aqueous brines is likely to be focused on more systematic generation of interaction models by utilizing quantum chemical as well as direct experimental measurements. New ion models need to be developed for use with the current generation of polarizable water models, including ion–ion interactions that will allow for accurate description of dense, mixed brines. Methods will need to be devised that go beyond the use of effective potentials for incorporation of quantum effects known to be important for water, and reactive force fields developed that can handle bond creation and breaking in systems with carbonate and silicate minerals. Lastly, another area of potential future work is the integration of molecular simulation methods in multiscale models for the chemical reactions leading to mineral dissolution and flow within the porous media in underground formations.« less

Virtual screening of B-Raf kinase inhibitors: A combination of pharmacophore modelling, molecular docking, 3D-QSAR model and binding free energy calculation studies.

PubMed

Zhang, Wen; Qiu, Kai-Xiong; Yu, Fang; Xie, Xiao-Guang; Zhang, Shu-Qun; Chen, Ya-Juan; Xie, Hui-Ding

2017-10-01

B-Raf kinase has been identified as an important target in recent cancer treatment. In order to discover structurally diverse and novel B-Raf inhibitors (BRIs), a virtual screening of BRIs against ZINC database was performed by using a combination of pharmacophore modelling, molecular docking, 3D-QSAR model and binding free energy (ΔG bind ) calculation studies in this work. After the virtual screening, six promising hit compounds were obtained, which were then tested for inhibitory activities of A375 cell lines. In the result, five hit compounds show good biological activities (IC 50 <50μM). The present method of virtual screening can be applied to find structurally diverse inhibitors, and the obtained five structurally diverse compounds are expected to develop novel BRIs. Copyright © 2017. Published by Elsevier Ltd.

Molecular docking and 3D-QSAR studies on inhibitors of DNA damage signaling enzyme human PARP-1.

PubMed

Fatima, Sabiha; Bathini, Raju; Sivan, Sree Kanth; Manga, Vijjulatha

2012-08-01

Poly (ADP-ribose) polymerase-1 (PARP-1) operates in a DNA damage signaling network. Molecular docking and three dimensional-quantitative structure activity relationship (3D-QSAR) studies were performed on human PARP-1 inhibitors. Docked conformation obtained for each molecule was used as such for 3D-QSAR analysis. Molecules were divided into a training set and a test set randomly in four different ways, partial least square analysis was performed to obtain QSAR models using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Derived models showed good statistical reliability that is evident from their r², q²(loo) and r²(pred) values. To obtain a consensus for predictive ability from all the models, average regression coefficient r²(avg) was calculated. CoMFA and CoMSIA models showed a value of 0.930 and 0.936, respectively. Information obtained from the best 3D-QSAR model was applied for optimization of lead molecule and design of novel potential inhibitors.

MIDG-Emerging grid technologies for multi-site preclinical molecular imaging research communities.

PubMed

Lee, Jasper; Documet, Jorge; Liu, Brent; Park, Ryan; Tank, Archana; Huang, H K

2011-03-01

Molecular imaging is the visualization and identification of specific molecules in anatomy for insight into metabolic pathways, tissue consistency, and tracing of solute transport mechanisms. This paper presents the Molecular Imaging Data Grid (MIDG) which utilizes emerging grid technologies in preclinical molecular imaging to facilitate data sharing and discovery between preclinical molecular imaging facilities and their collaborating investigator institutions to expedite translational sciences research. Grid-enabled archiving, management, and distribution of animal-model imaging datasets help preclinical investigators to monitor, access and share their imaging data remotely, and promote preclinical imaging facilities to share published imaging datasets as resources for new investigators. The system architecture of the Molecular Imaging Data Grid is described in a four layer diagram. A data model for preclinical molecular imaging datasets is also presented based on imaging modalities currently used in a molecular imaging center. The MIDG system components and connectivity are presented. And finally, the workflow steps for grid-based archiving, management, and retrieval of preclincial molecular imaging data are described. Initial performance tests of the Molecular Imaging Data Grid system have been conducted at the USC IPILab using dedicated VMware servers. System connectivity, evaluated datasets, and preliminary results are presented. The results show the system's feasibility, limitations, direction of future research. Translational and interdisciplinary research in medicine is increasingly interested in cellular and molecular biology activity at the preclinical levels, utilizing molecular imaging methods on animal models. The task of integrated archiving, management, and distribution of these preclinical molecular imaging datasets at preclinical molecular imaging facilities is challenging due to disparate imaging systems and multiple off-site investigators. A Molecular Imaging Data Grid design, implementation, and initial evaluation is presented to demonstrate the secure and novel data grid solution for sharing preclinical molecular imaging data across the wide-area-network (WAN).

Combined 3D-QSAR Modeling and Molecular Docking Studies on Pyrrole-Indolin-2-ones as Aurora A Kinase Inhibitors

PubMed Central

Ai, Yong; Wang, Shao-Teng; Sun, Ping-Hua; Song, Fa-Jun

2011-01-01

Aurora kinases have emerged as attractive targets for the design of anticancer drugs. 3D-QSAR (comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA)) and Surflex-docking studies were performed on a series of pyrrole-indoline-2-ones as Aurora A inhibitors. The CoMFA and CoMSIA models using 25 inhibitors in the training set gave r2cv values of 0.726 and 0.566, and r2 values of 0.972 and 0.984, respectively. The adapted alignment method with the suitable parameters resulted in reliable models. The contour maps produced by the CoMFA and CoMSIA models were employed to rationalize the key structural requirements responsible for the activity. Surflex-docking studies revealed that the sulfo group, secondary amine group on indolin-2-one, and carbonyl of 6,7-dihydro-1H-indol-4(5H)-one groups were significant for binding to the receptor, and some essential features were also identified. Based on the 3D-QSAR and docking results, a set of new molecules with high predicted activities were designed. PMID:21673910

Combined 3D-QSAR modeling and molecular docking studies on pyrrole-indolin-2-ones as Aurora A kinase inhibitors.

PubMed

Ai, Yong; Wang, Shao-Teng; Sun, Ping-Hua; Song, Fa-Jun

2011-01-01

Aurora kinases have emerged as attractive targets for the design of anticancer drugs. 3D-QSAR (comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA)) and Surflex-docking studies were performed on a series of pyrrole-indoline-2-ones as Aurora A inhibitors. The CoMFA and CoMSIA models using 25 inhibitors in the training set gave r(2) (cv) values of 0.726 and 0.566, and r(2) values of 0.972 and 0.984, respectively. The adapted alignment method with the suitable parameters resulted in reliable models. The contour maps produced by the CoMFA and CoMSIA models were employed to rationalize the key structural requirements responsible for the activity. Surflex-docking studies revealed that the sulfo group, secondary amine group on indolin-2-one, and carbonyl of 6,7-dihydro-1H-indol-4(5H)-one groups were significant for binding to the receptor, and some essential features were also identified. Based on the 3D-QSAR and docking results, a set of new molecules with high predicted activities were designed.

QSAR, molecular docking studies of thiophene and imidazopyridine derivatives as polo-like kinase 1 inhibitors

NASA Astrophysics Data System (ADS)

Cao, Shandong

2012-08-01

The purpose of the present study was to develop in silico models allowing for a reliable prediction of polo-like kinase inhibitors based on a large diverse dataset of 136 compounds. As an effective method, quantitative structure activity relationship (QSAR) was applied using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The proposed QSAR models showed reasonable predictivity of thiophene analogs (Rcv2=0.533, Rpred2=0.845) and included four molecular descriptors, namely IC3, RDF075m, Mor02m and R4e+. The optimal model for imidazopyridine derivatives (Rcv2=0.776, Rpred2=0.876) was shown to perform good in prediction accuracy, using GATS2m and BEHe1 descriptors. Analysis of the contour maps helped to identify structural requirements for the inhibitors and served as a basis for the design of the next generation of the inhibitor analogues. Docking studies were also employed to position the inhibitors into the polo-like kinase active site to determine the most probable binding mode. These studies may help to understand the factors influencing the binding affinity of chemicals and to develop alternative methods for prescreening and designing of polo-like kinase inhibitors.

Antidepressant-like activity of venlafaxine and clonidine in mice exposed to single prolonged stress - A model of post-traumatic stress disorder. Pharmacodynamic and molecular docking studies.

PubMed

Malikowska, Natalia; Fijałkowski, Łukasz; Nowaczyk, Alicja; Popik, Piotr; Sałat, Kinga

2017-10-15

Post-traumatic stress disorder (PTSD) is a growing issue worldwide characterized by stress and anxiety in response to re-experiencing traumatic events which strongly impair patient's quality of life and social functions. Available antidepressant and anxiolytic drugs are not efficacious in the majority of treated individuals. This necessitates a significant medical demand to develop novel therapeutic strategies for PTSD. Animal model of PTSD was induced using a mouse single prolonged stress protocol (mSPS). To assess the activity of venlafaxine and clonidine, the forced swim test (FST) was used repeatedly 24h, 3days, 8days, 15days and 25days after mSPS. To get insight into a possible mechanism of anti-PTSD action, molecular docking procedure was utilized for the most active drug. This in silico part comprised molecular docking of enantiomers of venlafaxine to human transporters for serotonin (hSERT), norepinephrine (hNET) and dopamine (hDAT). In mSPS-subjected mice FST revealed the effectiveness of venlafaxine, however in non SPS-subjected mice both venlafaxine and clonidine were active. Molecular docking studies indicated that the affinity of venlafaxine to monoamine transporters is growing in the following rank order: hDAT

Use of molecular modeling aided design to dial out hERG liability in adenosine A(2A) receptor antagonists.

PubMed

Deng, Qiaolin; Lim, Yeon-Hee; Anand, Rajan; Yu, Younong; Kim, Jae-hun; Zhou, Wei; Zheng, Junying; Tempest, Paul; Levorse, Dorothy; Zhang, Xiaoping; Greene, Scott; Mullins, Deborra; Culberson, Chris; Sherborne, Brad; Parker, Eric M; Stamford, Andrew; Ali, Amjad

2015-08-01

Molecular modeling was performed on a triazolo quinazoline lead compound to help develop a series of adenosine A2A receptor antagonists with improved hERG profile. Superposition of the lead compound onto MK-499, a benchmark hERG inhibitor, combined with pKa calculations and measurement, identified terminal fluorobenzene to be responsible for hERG activity. Docking of the lead compound into an A2A crystal structure suggested that this group is located at a flexible, spacious, and solvent-exposed opening of the binding pocket, making it possible to tolerate various functional groups. Transformation analysis (MMP, matched molecular pair) of in-house available experimental data on hERG provided suggestions for modifications in order to mitigate this liability. This led to the synthesis of a series of compounds with significantly reduced hERG activity. The strategy used in the modeling work can be applied to other medicinal chemistry programs to help improve hERG profile. Copyright © 2015 Elsevier Ltd. All rights reserved.

QTL analysis of ferric reductase activity in the model legume lotus japonicus

USDA-ARS?s Scientific Manuscript database

Physiological and molecular studies have demonstrated that iron accumulation from the soil into Strategy I plants can be limited by ferric reductase activity. An initial study of Lotus japonicus ecotypes Miyakojima MG-20 and Gifu B-129 identified significant leaf chlorosis and ferric reductase activ...

Dynamic Transcription Factor Networks in Epithelial-Mesenchymal Transition in Breast Cancer Models

PubMed Central

Siletz, Anaar; Schnabel, Michael; Kniazeva, Ekaterina; Schumacher, Andrew J.; Shin, Seungjin; Jeruss, Jacqueline S.; Shea, Lonnie D.

2013-01-01

The epithelial-mesenchymal transition (EMT) is a complex change in cell differentiation that allows breast carcinoma cells to acquire invasive properties. EMT involves a cascade of regulatory changes that destabilize the epithelial phenotype and allow mesenchymal features to manifest. As transcription factors (TFs) are upstream effectors of the genome-wide expression changes that result in phenotypic change, understanding the sequential changes in TF activity during EMT provides rich information on the mechanism of this process. Because molecular interactions will vary as cells progress from an epithelial to a mesenchymal differentiation program, dynamic networks are needed to capture the changing context of molecular processes. In this study we applied an emerging high-throughput, dynamic TF activity array to define TF activity network changes in three cell-based models of EMT in breast cancer based on HMLE Twist ER and MCF-7 mammary epithelial cells. The TF array distinguished conserved from model-specific TF activity changes in the three models. Time-dependent data was used to identify pairs of TF activities with significant positive or negative correlation, indicative of interdependent TF activity throughout the six-day study period. Dynamic TF activity patterns were clustered into groups of TFs that change along a time course of gene expression changes and acquisition of invasive capacity. Time-dependent TF activity data was combined with prior knowledge of TF interactions to construct dynamic models of TF activity networks as epithelial cells acquire invasive characteristics. These analyses show EMT from a unique and targetable vantage and may ultimately contribute to diagnosis and therapy. PMID:23593114

Dynamic transcription factor networks in epithelial-mesenchymal transition in breast cancer models.

PubMed

Siletz, Anaar; Schnabel, Michael; Kniazeva, Ekaterina; Schumacher, Andrew J; Shin, Seungjin; Jeruss, Jacqueline S; Shea, Lonnie D

2013-01-01

The epithelial-mesenchymal transition (EMT) is a complex change in cell differentiation that allows breast carcinoma cells to acquire invasive properties. EMT involves a cascade of regulatory changes that destabilize the epithelial phenotype and allow mesenchymal features to manifest. As transcription factors (TFs) are upstream effectors of the genome-wide expression changes that result in phenotypic change, understanding the sequential changes in TF activity during EMT provides rich information on the mechanism of this process. Because molecular interactions will vary as cells progress from an epithelial to a mesenchymal differentiation program, dynamic networks are needed to capture the changing context of molecular processes. In this study we applied an emerging high-throughput, dynamic TF activity array to define TF activity network changes in three cell-based models of EMT in breast cancer based on HMLE Twist ER and MCF-7 mammary epithelial cells. The TF array distinguished conserved from model-specific TF activity changes in the three models. Time-dependent data was used to identify pairs of TF activities with significant positive or negative correlation, indicative of interdependent TF activity throughout the six-day study period. Dynamic TF activity patterns were clustered into groups of TFs that change along a time course of gene expression changes and acquisition of invasive capacity. Time-dependent TF activity data was combined with prior knowledge of TF interactions to construct dynamic models of TF activity networks as epithelial cells acquire invasive characteristics. These analyses show EMT from a unique and targetable vantage and may ultimately contribute to diagnosis and therapy.

Advantages and limitations of classic and 3D QSAR approaches in nano-QSAR studies based on biological activity of fullerene derivatives

DOE PAGES

Jagiello, Karolina; Grzonkowska, Monika; Swirog, Marta; ...

2016-08-29

In this contribution, the advantages and limitations of two computational techniques that can be used for the investigation of nanoparticles activity and toxicity: classic nano-QSAR (Quantitative Structure–Activity Relationships employed for nanomaterials) and 3D nano-QSAR (three-dimensional Quantitative Structure–Activity Relationships, such us Comparative Molecular Field Analysis, CoMFA/Comparative Molecular Similarity Indices Analysis, CoMSIA analysis employed for nanomaterials) have been briefly summarized. Both approaches were compared according to the selected criteria, including: efficiency, type of experimental data, class of nanomaterials, time required for calculations and computational cost, difficulties in the interpretation. Taking into account the advantages and limitations of each method, we provide themore » recommendations for nano-QSAR modellers and QSAR model users to be able to determine a proper and efficient methodology to investigate biological activity of nanoparticles in order to describe the underlying interactions in the most reliable and useful manner.« less

Advantages and limitations of classic and 3D QSAR approaches in nano-QSAR studies based on biological activity of fullerene derivatives

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jagiello, Karolina; Grzonkowska, Monika; Swirog, Marta

In this contribution, the advantages and limitations of two computational techniques that can be used for the investigation of nanoparticles activity and toxicity: classic nano-QSAR (Quantitative Structure–Activity Relationships employed for nanomaterials) and 3D nano-QSAR (three-dimensional Quantitative Structure–Activity Relationships, such us Comparative Molecular Field Analysis, CoMFA/Comparative Molecular Similarity Indices Analysis, CoMSIA analysis employed for nanomaterials) have been briefly summarized. Both approaches were compared according to the selected criteria, including: efficiency, type of experimental data, class of nanomaterials, time required for calculations and computational cost, difficulties in the interpretation. Taking into account the advantages and limitations of each method, we provide themore » recommendations for nano-QSAR modellers and QSAR model users to be able to determine a proper and efficient methodology to investigate biological activity of nanoparticles in order to describe the underlying interactions in the most reliable and useful manner.« less

Comparative molecular field analysis and molecular docking studies on novel aryl chalcone derivatives against an important drug target cysteine protease in Plasmodium falciparum.

PubMed

Thillainayagam, Mahalakshmi; Anbarasu, Anand; Ramaiah, Sudha

2016-08-21

The computational studies namely molecular docking simulations and Comparative Molecular Field Analysis (CoMFA) are executed on series of 52 novel aryl chalcones derivatives using Plasmodium falciparum cysteine proteases (falcipain - 2) as vital target. In the present study, the correlation between different molecular field effects namely steric and electrostatic interactions and chemical structures to the inhibitory activities of novel aryl chalcone derivatives is inferred to perceive the major structural prerequisites for the rational design and development of potent and novel lead anti-malarial compound. The apparent binding conformations of all the compounds at the active site of falcipain - 2 and the hydrogen-bond interactions which could be used to modify the inhibitory activities are identified by using Surflex-dock study. Statistically significant CoMFA model has been developed with the cross-validated correlation coefficient (q(2)) of 0.912 and the non-cross-validated correlation coefficient (r(2)) of 0.901. Standard error of estimation (SEE) of 0.210, with the optimum number of components is ten. The predictability of the derived model is examined with a test set consists of sixteen compounds and the predicted r(2) value is found to be 0.924. The docking and QSAR study results confer crucial suggestions for the optimization of novel 1,3-diphenyl-2-propen-1-one derivatives and synthesis of effective anti- malarial compounds. Copyright © 2016 Elsevier Ltd. All rights reserved.

Molecular modeling and identification of novel glucokinase activators through stepwise virtual screening.

PubMed

Behera, Pabitra Mohan; Behera, Deepak Kumar; Satpati, Suresh; Agnihotri, Geetanjali; Nayak, Sanghamitra; Padhi, Payodhar; Dixit, Anshuman

2015-04-01

The glucose phosphorylating enzyme glucokinase (GK) is a 50kD monomeric protein having 465 amino acids. It maintains glucose homeostasis inside cells, acts as a glucose sensor in pancreatic β-cells and as a rate controlling enzyme for hepatic glucose clearance and glycogen synthesis. It has two binding sites, one for binding d-glucose and the other for a putative allosteric activator named glucokinase activator (GKA). The GKAs interact with the same region of the GK enzyme that is commonly affected by naturally occurring mutations in humans. However, many GKAs do not bind to GK in the absence of glucose. Recently, it has been reported that GKAs are highly effective in patients with type 2 diabetes mellitus. In this milieu a molecular modeling study has been carried out on three natural variants of GK that lie in the GKA binding site and are known to cause maturity onset diabetes of young (MODY). Additionally, a 10ns molecular dynamics simulation was done on each of the modeled variant in order to explore the flexibility of this site. Subsequently, a systematic virtual screening study was done to identify compounds which can bind with high affinity at GKA binding site of mutant GK. Copyright © 2015 Elsevier Inc. All rights reserved.

Molecular mechanisms of liver ischemia reperfusion injury: Insights from transgenic knockout models

PubMed Central

Datta, Gourab; Fuller, Barry J; Davidson, Brian R

2013-01-01

Ischemia reperfusion injury is a major obstacle in liver resection and liver transplantation surgery. Understanding the mechanisms of liver ischemia reperfusion injury (IRI) and developing strategies to counteract this injury will therefore reduce acute complications in hepatic resection and transplantation, as well as expanding the potential pool of usable donor grafts. The initial liver injury is initiated by reactive oxygen species which cause direct cellular injury and also activate a cascade of molecular mediators leading to microvascular changes, increased apoptosis and acute inflammatory changes with increased hepatocyte necrosis. Some adaptive pathways are activated during reperfusion that reduce the reperfusion injury. IRI involves a complex interplay between neutrophils, natural killer T-cells cells, CD4+ T cell subtypes, cytokines, nitric oxide synthases, haem oxygenase-1, survival kinases such as the signal transducer and activator of transcription, Phosphatidylinositol 3-kinases/Akt and nuclear factor κβ pathways. Transgenic animals, particularly genetic knockout models, have become a powerful tool at elucidating mechanisms of liver ischaemia reperfusion injury and are complementary to pharmacological studies. Targeted disruption of the protein at the genetic level is more specific and maintained than pharmacological inhibitors or stimulants of the same protein. This article reviews the evidence from knockout models of liver IRI about the cellular and molecular mechanisms underlying liver IRI. PMID:23555157

Mathematical Justification of Expression-Based Pathway Activation Scoring (PAS).

PubMed

Aliper, Alexander M; Korzinkin, Michael B; Kuzmina, Natalia B; Zenin, Alexander A; Venkova, Larisa S; Smirnov, Philip Yu; Zhavoronkov, Alex A; Buzdin, Anton A; Borisov, Nikolay M

2017-01-01

Although modeling of activation kinetics for various cell signaling pathways has reached a high grade of sophistication and thoroughness, most such kinetic models still remain of rather limited practical value for biomedicine. Nevertheless, recent advancements have been made in application of signaling pathway science for real needs of prescription of the most effective drugs for individual patients. The methods for such prescription evaluate the degree of pathological changes in the signaling machinery based on two types of data: first, on the results of high-throughput gene expression profiling, and second, on the molecular pathway graphs that reflect interactions between the pathway members. For example, our algorithm OncoFinder evaluates the activation of molecular pathways on the basis of gene/protein expression data in the objects of the interest.Yet, the question of assessment of the relative importance for each gene product in a molecular pathway remains unclear unless one call for the methods of parameter sensitivity /stiffness analysis in the interactomic kinetic models of signaling pathway activation in terms of total concentrations of each gene product.Here we show two principal points: 1. First, the importance coefficients for each gene in pathways that were obtained using the extremely time- and labor-consuming stiffness analysis of full-scaled kinetic models generally differ from much easier-to-calculate expression-based pathway activation score (PAS) not more than by 30%, so the concept of PAS is kinetically justified. 2. Second, the use of pathway-based approach instead of distinct gene analysis, due to the law of large numbers, allows restoring the correlation between the similar samples that were examined using different transcriptome investigation techniques.

Surface similarity-based molecular query-retrieval

PubMed Central

Singh, Rahul

2007-01-01

Background Discerning the similarity between molecules is a challenging problem in drug discovery as well as in molecular biology. The importance of this problem is due to the fact that the biochemical characteristics of a molecule are closely related to its structure. Therefore molecular similarity is a key notion in investigations targeting exploration of molecular structural space, query-retrieval in molecular databases, and structure-activity modelling. Determining molecular similarity is related to the choice of molecular representation. Currently, representations with high descriptive power and physical relevance like 3D surface-based descriptors are available. Information from such representations is both surface-based and volumetric. However, most techniques for determining molecular similarity tend to focus on idealized 2D graph-based descriptors due to the complexity that accompanies reasoning with more elaborate representations. Results This paper addresses the problem of determining similarity when molecules are described using complex surface-based representations. It proposes an intrinsic, spherical representation that systematically maps points on a molecular surface to points on a standard coordinate system (a sphere). Molecular surface properties such as shape, field strengths, and effects due to field super-positioningcan then be captured as distributions on the surface of the sphere. Surface-based molecular similarity is subsequently determined by computing the similarity of the surface-property distributions using a novel formulation of histogram-intersection. The similarity formulation is not only sensitive to the 3D distribution of the surface properties, but is also highly efficient to compute. Conclusion The proposed method obviates the computationally expensive step of molecular pose-optimisation, can incorporate conformational variations, and facilitates highly efficient determination of similarity by directly comparing molecular surfaces and surface-based properties. Retrieval performance, applications in structure-activity modeling of complex biological properties, and comparisons with existing research and commercial methods demonstrate the validity and effectiveness of the approach. PMID:17634096

Water diffusion in silicate glasses: the effect of glass structure

NASA Astrophysics Data System (ADS)

Kuroda, M.; Tachibana, S.

2016-12-01

Water diffusion in silicate melts (glasses) is one of the main controlling factors of magmatism in a volcanic system. Water diffusivity in silicate glasses depends on its own concentration. However, the mechanism causing those dependences has not been fully understood yet. In order to construct a general model for water diffusion in various silicate glasses, we performed water diffusion experiments in silica glass and proposed a new water diffusion model [Kuroda et al., 2015]. In the model, water diffusivity is controlled by the concentration of both main diffusion species (i.e. molecular water) and diffusion pathways, which are determined by the concentrations of hydroxyl groups and network modifier cations. The model well explains the water diffusivity in various silicate glasses from silica glass to basalt glass. However, pre-exponential factors of water diffusivity in various glasses show five orders of magnitude variations although the pre-exponential factor should ideally represent the jump frequency and the jump distance of molecular water and show a much smaller variation. Here, we attribute the large variation of pre-exponential factors to a glass structure dependence of activation energy for molecular water diffusion. It has been known that the activation energy depends on the water concentration [Nowak and Behrens, 1997]. The concentration of hydroxyls, which cut Si-O-Si network in the glass structure, increases with water concentration, resulting in lowering the activation energy for water diffusion probably due to more fragmented structure. Network modifier cations are likely to play the same role as water. With taking the effect of glass structure into account, we found that the variation of pre-exponential factors of water diffusivity in silicate glasses can be much smaller than the five orders of magnitude, implying that the diffusion of molecular water in silicate glasses is controlled by the same atomic process.

Molecular modeling and snake venom phospholipase A2 inhibition by phenolic compounds: Structure-activity relationship.

PubMed

Alam, Md Iqbal; Alam, Mohammed A; Alam, Ozair; Nargotra, Amit; Taneja, Subhash Chandra; Koul, Surrinder

2016-05-23

In our earlier study, we have reported that a phenolic compound 2-hydroxy-4-methoxybenzaldehyde from Janakia arayalpatra root extract was active against Viper and Cobra envenomations. Based on the structure of this natural product, libraries of synthetic structurally variant phenolic compounds were studied through molecular docking on the venom protein. To validate the activity of eight selected compounds, we have tested them in in vivo and in vitro models. The compound 21 (2-hydroxy-3-methoxy benzaldehyde), 22 (2-hydroxy-4-methoxybenzaldehyde) and 35 (2-hydroxy-3-methoxybenzylalcohol) were found to be active against venom-induced pathophysiological changes. The compounds 20, 15 and 35 displayed maximum anti-hemorrhagic, anti-lethal and PLA2 inhibitory activity respectively. In terms of SAR, the presence of a formyl group in conjunction with a phenolic group was seen as a significant contributor towards increasing the antivenom activity. The above observations confirmed the anti-venom activity of the phenolic compounds which needs to be further investigated for the development of new anti-snake venom leads. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Benefits of statistical molecular design, covariance analysis, and reference models in QSAR: a case study on acetylcholinesterase

NASA Astrophysics Data System (ADS)

Andersson, C. David; Hillgren, J. Mikael; Lindgren, Cecilia; Qian, Weixing; Akfur, Christine; Berg, Lotta; Ekström, Fredrik; Linusson, Anna

2015-03-01

Scientific disciplines such as medicinal- and environmental chemistry, pharmacology, and toxicology deal with the questions related to the effects small organic compounds exhort on biological targets and the compounds' physicochemical properties responsible for these effects. A common strategy in this endeavor is to establish structure-activity relationships (SARs). The aim of this work was to illustrate benefits of performing a statistical molecular design (SMD) and proper statistical analysis of the molecules' properties before SAR and quantitative structure-activity relationship (QSAR) analysis. Our SMD followed by synthesis yielded a set of inhibitors of the enzyme acetylcholinesterase (AChE) that had very few inherent dependencies between the substructures in the molecules. If such dependencies exist, they cause severe errors in SAR interpretation and predictions by QSAR-models, and leave a set of molecules less suitable for future decision-making. In our study, SAR- and QSAR models could show which molecular sub-structures and physicochemical features that were advantageous for the AChE inhibition. Finally, the QSAR model was used for the prediction of the inhibition of AChE by an external prediction set of molecules. The accuracy of these predictions was asserted by statistical significance tests and by comparisons to simple but relevant reference models.

Interactions of dendrimers with biological drug targets: reality or mystery - a gap in drug delivery and development research.

PubMed

Ahmed, Shaimaa; Vepuri, Suresh B; Kalhapure, Rahul S; Govender, Thirumala

2016-07-21

Dendrimers have emerged as novel and efficient materials that can be used as therapeutic agents/drugs or as drug delivery carriers to enhance therapeutic outcomes. Molecular dendrimer interactions are central to their applications and realising their potential. The molecular interactions of dendrimers with drugs or other materials in drug delivery systems or drug conjugates have been extensively reported in the literature. However, despite the growing application of dendrimers as biologically active materials, research focusing on the mechanistic analysis of dendrimer interactions with therapeutic biological targets is currently lacking in the literature. This comprehensive review on dendrimers over the last 15 years therefore attempts to identify the reasons behind the apparent lack of dendrimer-receptor research and proposes approaches to address this issue. The structure, hierarchy and applications of dendrimers are briefly highlighted, followed by a review of their various applications, specifically as biologically active materials, with a focus on their interactions at the target site. It concludes with a technical guide to assist researchers on how to employ various molecular modelling and computational approaches for research on dendrimer interactions with biological targets at a molecular level. This review highlights the impact of a mechanistic analysis of dendrimer interactions on a molecular level, serves to guide and optimise their discovery as medicinal agents, and hopes to stimulate multidisciplinary research between scientific, experimental and molecular modelling research teams.

In Silico Characterization of the Binding Affinity of Dendrimers to Penicillin-Binding Proteins (PBPs): Can PBPs be Potential Targets for Antibacterial Dendrimers?

PubMed

Ahmed, Shaimaa; Vepuri, Suresh B; Ramesh, Muthusamy; Kalhapure, Rahul; Suleman, Nadia; Govender, Thirumala

2016-04-01

We have shown that novel silver salts of poly (propyl ether) imine (PETIM) dendron and dendrimers developed in our group exhibit preferential antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus aureus. This led us to examine whether molecular modeling methods could be used to identify the key structural design principles for a bioactive lead molecule, explore the mechanism of binding with biological targets, and explain their preferential antibacterial activity. The current article reports the conformational landscape as well as mechanism of binding of generation 1 PETIM dendron and dendrimers to penicillin-binding proteins (PBPs) in order to understand the antibacterial activity profiles of their silver salts. Molecular dynamics at different simulation protocols and conformational analysis were performed to elaborate on the conformational features of the studied dendrimers, as well as to create the initial structure for further binding studies. The results showed that for all compounds, there were no significant conformational changes due to variation in simulation conditions. Molecular docking calculations were performed to investigate the binding theme between the studied dendrimers and PBPs. Interestingly, in significant accordance with the experimental data, dendron and dendrimer with aliphatic cores were found to show higher activity against S. aureus than the dendrimer with an aromatic core. The latter showed higher activity against MRSA. The findings from this computational and molecular modeling report together with the experimental results serve as a road map toward designing more potent antibacterial dendrimers against resistant bacterial strains.

V-ATPase proton pumping activity is required for adult zebrafish appendage regeneration.

PubMed

Monteiro, Joana; Aires, Rita; Becker, Jörg D; Jacinto, António; Certal, Ana C; Rodríguez-León, Joaquín

2014-01-01

The activity of ion channels and transporters generates ion-specific fluxes that encode electrical and/or chemical signals with biological significance. Even though it is long known that some of those signals are crucial for regeneration, only in recent years the corresponding molecular sources started to be identified using mainly invertebrate or larval vertebrate models. We used adult zebrafish caudal fin as a model to investigate which and how ion transporters affect regeneration in an adult vertebrate model. Through the combined use of biophysical and molecular approaches, we show that V-ATPase activity contributes to a regeneration-specific H+ ef`flux. The onset and intensity of both V-ATPase expression and H+ efflux correlate with the different regeneration rate along the proximal-distal axis. Moreover, we show that V-ATPase inhibition impairs regeneration in adult vertebrate. Notably, the activity of this H+ pump is necessary for aldh1a2 and mkp3 expression, blastema cell proliferation and fin innervation. To the best of our knowledge, this is the first report on the role of V-ATPase during adult vertebrate regeneration.

V-ATPase Proton Pumping Activity Is Required for Adult Zebrafish Appendage Regeneration

PubMed Central

Monteiro, Joana; Aires, Rita; Becker, Jörg D.; Jacinto, António; Certal, Ana C.; Rodríguez-León, Joaquín

2014-01-01

The activity of ion channels and transporters generates ion-specific fluxes that encode electrical and/or chemical signals with biological significance. Even though it is long known that some of those signals are crucial for regeneration, only in recent years the corresponding molecular sources started to be identified using mainly invertebrate or larval vertebrate models. We used adult zebrafish caudal fin as a model to investigate which and how ion transporters affect regeneration in an adult vertebrate model. Through the combined use of biophysical and molecular approaches, we show that V-ATPase activity contributes to a regeneration-specific H+ ef`flux. The onset and intensity of both V-ATPase expression and H+ efflux correlate with the different regeneration rate along the proximal-distal axis. Moreover, we show that V-ATPase inhibition impairs regeneration in adult vertebrate. Notably, the activity of this H+ pump is necessary for aldh1a2 and mkp3 expression, blastema cell proliferation and fin innervation. To the best of our knowledge, this is the first report on the role of V-ATPase during adult vertebrate regeneration. PMID:24671205

Alarmin S100A8/S100A9 as a biomarker for molecular imaging of local inflammatory activity.

PubMed

Vogl, Thomas; Eisenblätter, Michel; Völler, Tom; Zenker, Stefanie; Hermann, Sven; van Lent, Peter; Faust, Andreas; Geyer, Christiane; Petersen, Beatrix; Roebrock, Kirsten; Schäfers, Michael; Bremer, Christoph; Roth, Johannes

2014-08-06

Inflammation has a key role in the pathogenesis of various human diseases. The early detection, localization and monitoring of inflammation are crucial for tailoring individual therapies. However, reliable biomarkers to detect local inflammatory activities and to predict disease outcome are still missing. Alarmins, which are locally released during cellular stress, are early amplifiers of inflammation. Here, using optical molecular imaging, we demonstrate that the alarmin S100A8/S100A9 serves as a sensitive local and systemic marker for the detection of even sub-clinical disease activity in inflammatory and immunological processes like irritative and allergic contact dermatitis. In a model of collagen-induced arthritis, we use S100A8/S100A9 imaging to predict the development of disease activity. Furthermore, S100A8/S100A9 can act as a very early and sensitive biomarker in experimental leishmaniasis for phagocyte activation linked to an effective Th1-response. In conclusion, the alarmin S100A8/S100A9 is a valuable and sensitive molecular target for novel imaging approaches to monitor clinically relevant inflammatory disorders on a molecular level.

A machine learning approach to computer-aided molecular design

NASA Astrophysics Data System (ADS)

Bolis, Giorgio; Di Pace, Luigi; Fabrocini, Filippo

1991-12-01

Preliminary results of a machine learning application concerning computer-aided molecular design applied to drug discovery are presented. The artificial intelligence techniques of machine learning use a sample of active and inactive compounds, which is viewed as a set of positive and negative examples, to allow the induction of a molecular model characterizing the interaction between the compounds and a target molecule. The algorithm is based on a twofold phase. In the first one — the specialization step — the program identifies a number of active/inactive pairs of compounds which appear to be the most useful in order to make the learning process as effective as possible and generates a dictionary of molecular fragments, deemed to be responsible for the activity of the compounds. In the second phase — the generalization step — the fragments thus generated are combined and generalized in order to select the most plausible hypothesis with respect to the sample of compounds. A knowledge base concerning physical and chemical properties is utilized during the inductive process.

Removal of carbamazepine and clofibric acid from water using double templates-molecularly imprinted polymers.

PubMed

Dai, Chao-meng; Zhang, Juan; Zhang, Ya-lei; Zhou, Xue-fei; Duan, Yan-ping; Liu, Shu-guang

2013-08-01

A novel double templates-molecularly imprinted polymer (MIP) was prepared by precipitation polymerization using carbamazepine (CBZ) and clofibric acid (CA) as the double templates molecular and 2-vinylpyridine as functional monomer. The equilibrium data of MIP was well described by the Freundlich isotherm model. Two kinetic models were adopted to describe the experimental data, and the pseudo second-order model well-described adsorption of CBZ and CA on the MIP. Adsorption experimental results showed that the MIP had good selectivity and adsorption capacity for CBZ and CA in the presence of competitive compounds compared with non-imprinted polymer, commercial powdered activated carbon, and C18 adsorbents. The feasibility of removing CBZ and CA from water by the MIP was demonstrated using tap water, lake water, and river water.

Chronic activation of wild-type epidermal growth factor receptor and loss of Cdkn2a cause mouse glioblastoma formation.

PubMed

Acquaviva, Jaime; Jun, Hyun Jung; Lessard, Julie; Ruiz, Rolando; Zhu, Haihao; Donovan, Melissa; Woolfenden, Steve; Boskovitz, Abraham; Raval, Ami; Bronson, Roderick T; Pfannl, Rolf; Whittaker, Charles A; Housman, David E; Charest, Al

2011-12-01

Glioblastoma multiforme (GBM) is characterized by overexpression of epidermal growth factor receptor (EGFR) and loss of the tumor suppressors Ink4a/Arf. Efforts at modeling GBM using wild-type EGFR in mice have proven unsuccessful. Here, we present a unique mouse model of wild-type EGFR-driven gliomagenesis. We used a combination of somatic conditional overexpression and ligand-mediated chronic activation of EGFR in cooperation with Ink4a/Arf loss in the central nervous system of adult mice to generate tumors with the histopathologic and molecular characteristics of human GBMs. Sustained, ligand-mediated activation of EGFR was necessary for gliomagenesis, functionally substantiating the clinical observation that EGFR-positive GBMs from patients express EGFR ligands. To gain a better understanding of the clinically disappointing EGFR-targeted therapies for GBM, we investigated the molecular responses to EGFR tyrosine kinase inhibitor (TKI) treatment in this model. Gefitinib treatment of primary GBM cells resulted in a robust apoptotic response, partially conveyed by mitogen-activated protein kinase (MAPK) signaling attenuation and accompanied by BIM(EL) expression. In human GBMs, loss-of-function mutations in the tumor suppressor PTEN are a common occurrence. Elimination of PTEN expression in GBM cells posttumor formation did not confer resistance to TKI treatment, showing that PTEN status in our model is not predictive. Together, these findings offer important mechanistic insights into the genetic determinants of EGFR gliomagenesis and sensitivity to TKIs and provide a robust discovery platform to better understand the molecular events that are associated with predictive markers of TKI therapy.

Three-dimensional quantitative structure-activity relationship studies on novel series of benzotriazine based compounds acting as Src inhibitors using CoMFA and CoMSIA.

PubMed

Gueto, Carlos; Ruiz, José L; Torres, Juan E; Méndez, Jefferson; Vivas-Reyes, Ricardo

2008-03-01

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of benzotriazine derivatives, as Src inhibitors. Ligand molecular superimposition on the template structure was performed by database alignment method. The statistically significant model was established of 72 molecules, which were validated by a test set of six compounds. The CoMFA model yielded a q(2)=0.526, non cross-validated R(2) of 0.781, F value of 88.132, bootstrapped R(2) of 0.831, standard error of prediction=0.587, and standard error of estimate=0.351 while the CoMSIA model yielded the best predictive model with a q(2)=0.647, non cross-validated R(2) of 0.895, F value of 115.906, bootstrapped R(2) of 0.953, standard error of prediction=0.519, and standard error of estimate=0.178. The contour maps obtained from 3D-QSAR studies were appraised for activity trends for the molecules analyzed. Results indicate that small steric volumes in the hydrophobic region, electron-withdrawing groups next to the aryl linker region, and atoms close to the solvent accessible region increase the Src inhibitory activity of the compounds. In fact, adding substituents at positions 5, 6, and 8 of the benzotriazine nucleus were generated new compounds having a higher predicted activity. The data generated from the present study will further help to design novel, potent, and selective Src inhibitors as anticancer therapeutic agents.

Intramolecular hydrophobic interactions are critical mediators of STAT5 dimerization

NASA Astrophysics Data System (ADS)

Fahrenkamp, Dirk; Li, Jinyu; Ernst, Sabrina; Schmitz-van de Leur, Hildegard; Chatain, Nicolas; Küster, Andrea; Koschmieder, Steffen; Lüscher, Bernhard; Rossetti, Giulia; Müller-Newen, Gerhard

2016-10-01

STAT5 is an essential transcription factor in hematopoiesis, which is activated through tyrosine phosphorylation in response to cytokine stimulation. Constitutive activation of STAT5 is a hallmark of myeloid and lymphoblastic leukemia. Using homology modeling and molecular dynamics simulations, a model of the STAT5 phosphotyrosine-SH2 domain interface was generated providing first structural information on the activated STAT5 dimer including a sequence, for which no structural information is available for any of the STAT proteins. We identified a novel intramolecular interaction mediated through F706, adjacent to the phosphotyrosine motif, and a unique hydrophobic interface on the surface of the SH2 domain. Analysis of corresponding STAT5 mutants revealed that this interaction is dispensable for Epo receptor-mediated phosphorylation of STAT5 but essential for dimer formation and subsequent nuclear accumulation. Moreover, the herein presented model clarifies molecular mechanisms of recently discovered leukemic STAT5 mutants and will help to guide future drug development.

Intramolecular hydrophobic interactions are critical mediators of STAT5 dimerization

PubMed Central

Fahrenkamp, Dirk; Li, Jinyu; Ernst, Sabrina; Schmitz-Van de Leur, Hildegard; Chatain, Nicolas; Küster, Andrea; Koschmieder, Steffen; Lüscher, Bernhard; Rossetti, Giulia; Müller-Newen, Gerhard

2016-01-01

STAT5 is an essential transcription factor in hematopoiesis, which is activated through tyrosine phosphorylation in response to cytokine stimulation. Constitutive activation of STAT5 is a hallmark of myeloid and lymphoblastic leukemia. Using homology modeling and molecular dynamics simulations, a model of the STAT5 phosphotyrosine-SH2 domain interface was generated providing first structural information on the activated STAT5 dimer including a sequence, for which no structural information is available for any of the STAT proteins. We identified a novel intramolecular interaction mediated through F706, adjacent to the phosphotyrosine motif, and a unique hydrophobic interface on the surface of the SH2 domain. Analysis of corresponding STAT5 mutants revealed that this interaction is dispensable for Epo receptor-mediated phosphorylation of STAT5 but essential for dimer formation and subsequent nuclear accumulation. Moreover, the herein presented model clarifies molecular mechanisms of recently discovered leukemic STAT5 mutants and will help to guide future drug development. PMID:27752093

Relation between cooperative molecular motors and active Brownian particles.

PubMed

Touya, Clément; Schwalger, Tilo; Lindner, Benjamin

2011-05-01

Active Brownian particles (ABPs), obeying a nonlinear Langevin equation with speed-dependent drift and noise amplitude, are well-known models used to describe self-propelled motion in biology. In this paper we study a model describing the stochastic dynamics of a group of coupled molecular motors (CMMs). Using two independent numerical methods, one based on the stationary velocity distribution of the motors and the other one on the local increments (also known as the Kramers-Moyal coefficients) of the velocity, we establish a connection between the CMM and the ABP models. The parameters extracted for the ABP via the two methods show good agreement for both symmetric and asymmetric cases and are independent of N, the number of motors, provided that N is not too small. This indicates that one can indeed describe the CMM problem with a simpler ABP model. However, the power spectrum of velocity fluctuations in the CMM model reveals a peak at a finite frequency, a peak which is absent in the velocity spectrum of the ABP model. This implies richer dynamic features of the CMM model which cannot be captured by an ABP model.

Relation between cooperative molecular motors and active Brownian particles

NASA Astrophysics Data System (ADS)

Touya, Clément; Schwalger, Tilo; Lindner, Benjamin

2011-05-01

Active Brownian particles (ABPs), obeying a nonlinear Langevin equation with speed-dependent drift and noise amplitude, are well-known models used to describe self-propelled motion in biology. In this paper we study a model describing the stochastic dynamics of a group of coupled molecular motors (CMMs). Using two independent numerical methods, one based on the stationary velocity distribution of the motors and the other one on the local increments (also known as the Kramers-Moyal coefficients) of the velocity, we establish a connection between the CMM and the ABP models. The parameters extracted for the ABP via the two methods show good agreement for both symmetric and asymmetric cases and are independent of N, the number of motors, provided that N is not too small. This indicates that one can indeed describe the CMM problem with a simpler ABP model. However, the power spectrum of velocity fluctuations in the CMM model reveals a peak at a finite frequency, a peak which is absent in the velocity spectrum of the ABP model. This implies richer dynamic features of the CMM model which cannot be captured by an ABP model.

Design, synthesis of allosteric peptide activator for human SIRT1 and its biological evaluation in cellular model of Alzheimer's disease.

PubMed

Kumar, Rahul; Nigam, Lokesh; Singh, Amrendra Pratap; Singh, Kusum; Subbarao, Naidu; Dey, Sharmistha

2017-02-15

Sirtuin 1 (SIRT1) is one of the member of the mammalian proteins of the Sirtuin family of NAD + dependent deacetylases, has recently been shown to attenuate amyloidogenic processing of amyloid protein precursor (APP) in in-vitro cell culture studies and transgenic mouse models of Alzheimer's disease (AD). SIRT1 has been shown to have a protective role against (AD). It has been reported earlier that increasing SIRT1 activity can prevent AD in mice model. Tripeptide as an activator of SIRT1 were screened on the basis of structural information by molecular docking and synthesized by solid phase method. The enhancement of biochemical activity of pure recombinant SIRT1 as well as SIRT1 in serum of AD patients in presence of tripeptide was done by Fluorescent Activity Assay. The activity of SIRT1 by peptide was assessed in IMR-32 cell line by measuring acetylated p53 level. Further the protective effect of SIRT1 activator in cellular model of AD was analyzed by MTT assay. We find CWR tripeptide as a SIRT1 activator by molecular docking, enhanced the activity of SIRT1 protein by lowering the Michaelis constant, Km by allosteric mechanism. The activity of serum SIRT1 of AD was also increases by CWR. It also decreased the acetylation of p53 in IMR32 neuroblastoma cells and protected the cell death caused by Aβ amyloid fragments in cell line model of AD. Thus, it can be concluded that CWR may serve as platform to elucidate further small molecule activator as a therapeutic agent for AD targeting SIRT1. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Heterogeneously Catalyzed Endothermic Fuel Cracking

DTIC Science & Technology

2016-08-28

Much of this literature is in the context of gas -to- liquids technology and industrial dehydrogenation processes. Based on the published measurements...certain zeolites. Comparisons of conversion, major product distributions and molecular weight growth processes in the gas -phase pyrolysis of model...thereby maximizing the extent of cooling, (b) increase catalyst activity for fuel decomposition, but inhibit gas -phase molecular weight growth

Structural similarity based kriging for quantitative structure activity and property relationship modeling.

PubMed

Teixeira, Ana L; Falcao, Andre O

2014-07-28

Structurally similar molecules tend to have similar properties, i.e. closer molecules in the molecular space are more likely to yield similar property values while distant molecules are more likely to yield different values. Based on this principle, we propose the use of a new method that takes into account the high dimensionality of the molecular space, predicting chemical, physical, or biological properties based on the most similar compounds with measured properties. This methodology uses ordinary kriging coupled with three different molecular similarity approaches (based on molecular descriptors, fingerprints, and atom matching) which creates an interpolation map over the molecular space that is capable of predicting properties/activities for diverse chemical data sets. The proposed method was tested in two data sets of diverse chemical compounds collected from the literature and preprocessed. One of the data sets contained dihydrofolate reductase inhibition activity data, and the second molecules for which aqueous solubility was known. The overall predictive results using kriging for both data sets comply with the results obtained in the literature using typical QSPR/QSAR approaches. However, the procedure did not involve any type of descriptor selection or even minimal information about each problem, suggesting that this approach is directly applicable to a large spectrum of problems in QSAR/QSPR. Furthermore, the predictive results improve significantly with the similarity threshold between the training and testing compounds, allowing the definition of a confidence threshold of similarity and error estimation for each case inferred. The use of kriging for interpolation over the molecular metric space is independent of the training data set size, and no reparametrizations are necessary when more compounds are added or removed from the set, and increasing the size of the database will consequentially improve the quality of the estimations. Finally it is shown that this model can be used for checking the consistency of measured data and for guiding an extension of the training set by determining the regions of the molecular space for which new experimental measurements could be used to maximize the model's predictive performance.

Data-mining of potential antitubercular activities from molecular ingredients of traditional Chinese medicines.

PubMed

Jamal, Salma; Scaria, Vinod

2014-01-01

Background. Traditional Chinese medicine encompasses a well established alternate system of medicine based on a broad range of herbal formulations and is practiced extensively in the region for the treatment of a wide variety of diseases. In recent years, several reports describe in depth studies of the molecular ingredients of traditional Chinese medicines on the biological activities including anti-bacterial activities. The availability of a well-curated dataset of molecular ingredients of traditional Chinese medicines and accurate in-silico cheminformatics models for data mining for antitubercular agents and computational filters to prioritize molecules has prompted us to search for potential hits from these datasets. Results. We used a consensus approach to predict molecules with potential antitubercular activities from a large dataset of molecular ingredients of traditional Chinese medicines available in the public domain. We further prioritized 160 molecules based on five computational filters (SMARTSfilter) so as to avoid potentially undesirable molecules. We further examined the molecules for permeability across Mycobacterial cell wall and for potential activities against non-replicating and drug tolerant Mycobacteria. Additional in-depth literature surveys for the reported antitubercular activities of the molecular ingredients and their sources were considered for drawing support to prioritization. Conclusions. Our analysis suggests that datasets of molecular ingredients of traditional Chinese medicines offer a new opportunity to mine for potential biological activities. In this report, we suggest a proof-of-concept methodology to prioritize molecules for further experimental assays using a variety of computational tools. We also additionally suggest that a subset of prioritized molecules could be used for evaluation for tuberculosis due to their additional effect against non-replicating tuberculosis as well as the additional hepato-protection offered by the source of these ingredients.

Data-mining of potential antitubercular activities from molecular ingredients of traditional Chinese medicines

PubMed Central

Jamal, Salma

2014-01-01

Background. Traditional Chinese medicine encompasses a well established alternate system of medicine based on a broad range of herbal formulations and is practiced extensively in the region for the treatment of a wide variety of diseases. In recent years, several reports describe in depth studies of the molecular ingredients of traditional Chinese medicines on the biological activities including anti-bacterial activities. The availability of a well-curated dataset of molecular ingredients of traditional Chinese medicines and accurate in-silico cheminformatics models for data mining for antitubercular agents and computational filters to prioritize molecules has prompted us to search for potential hits from these datasets. Results. We used a consensus approach to predict molecules with potential antitubercular activities from a large dataset of molecular ingredients of traditional Chinese medicines available in the public domain. We further prioritized 160 molecules based on five computational filters (SMARTSfilter) so as to avoid potentially undesirable molecules. We further examined the molecules for permeability across Mycobacterial cell wall and for potential activities against non-replicating and drug tolerant Mycobacteria. Additional in-depth literature surveys for the reported antitubercular activities of the molecular ingredients and their sources were considered for drawing support to prioritization. Conclusions. Our analysis suggests that datasets of molecular ingredients of traditional Chinese medicines offer a new opportunity to mine for potential biological activities. In this report, we suggest a proof-of-concept methodology to prioritize molecules for further experimental assays using a variety of computational tools. We also additionally suggest that a subset of prioritized molecules could be used for evaluation for tuberculosis due to their additional effect against non-replicating tuberculosis as well as the additional hepato-protection offered by the source of these ingredients. PMID:25081126

Synthesis, molecular modeling and evaluation of α-glucosidase inhibition activity of 3,4-dihydroxy piperidines.

PubMed

Kasturi, Siva Prasad; Surarapu, Sujatha; Uppalanchi, Srinivas; Dwivedi, Shubham; Yogeeswari, Perumal; Sigalapalli, Dilep Kumar; Bathini, Nagendra Babu; Ethiraj, Krishna S; Anireddy, Jaya Shree

2018-04-25

Biological evaluation of 3,4-dihydroxy piperidines as α-glucosidase inhibitors is being reported for the first time. Forty-five derivatives (amides, di-amides and sulfonamides) were made using cis and trans 3,4-dihydroxy piperidines to evaluate their α-glucosidase inhibition activity. Polar groups (-OH, -NH 2 ) on phenyl ring having derivatives 5i, 5l, 7g, 7i &12j showed excellent activity compared to standard references. Acarbose, Voglibose and Miglitol were used as standard references. Molecular docking simulations were done for compounds to identify important binding modes responsible for inhibition activity of α-glucosidase. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Sequential Application of Ligand and Structure Based Modeling Approaches to Index Chemicals for Their hH4R Antagonism

PubMed Central

Basile, Livia; Milardi, Danilo; Zeidan, Mouhammed; Raiyn, Jamal; Guccione, Salvatore; Rayan, Anwar

2014-01-01

The human histamine H4 receptor (hH4R), a member of the G-protein coupled receptors (GPCR) family, is an increasingly attractive drug target. It plays a key role in many cell pathways and many hH4R ligands are studied for the treatment of several inflammatory, allergic and autoimmune disorders, as well as for analgesic activity. Due to the challenging difficulties in the experimental elucidation of hH4R structure, virtual screening campaigns are normally run on homology based models. However, a wealth of information about the chemical properties of GPCR ligands has also accumulated over the last few years and an appropriate combination of these ligand-based knowledge with structure-based molecular modeling studies emerges as a promising strategy for computer-assisted drug design. Here, two chemoinformatics techniques, the Intelligent Learning Engine (ILE) and Iterative Stochastic Elimination (ISE) approach, were used to index chemicals for their hH4R bioactivity. An application of the prediction model on external test set composed of more than 160 hH4R antagonists picked from the chEMBL database gave enrichment factor of 16.4. A virtual high throughput screening on ZINC database was carried out, picking ∼4000 chemicals highly indexed as H4R antagonists' candidates. Next, a series of 3D models of hH4R were generated by molecular modeling and molecular dynamics simulations performed in fully atomistic lipid membranes. The efficacy of the hH4R 3D models in discrimination between actives and non-actives were checked and the 3D model with the best performance was chosen for further docking studies performed on the focused library. The output of these docking studies was a consensus library of 11 highly active scored drug candidates. Our findings suggest that a sequential combination of ligand-based chemoinformatics approaches with structure-based ones has the potential to improve the success rate in discovering new biologically active GPCR drugs and increase the enrichment factors in a synergistic manner. PMID:25330207

Sequential application of ligand and structure based modeling approaches to index chemicals for their hH4R antagonism.

PubMed

Pappalardo, Matteo; Shachaf, Nir; Basile, Livia; Milardi, Danilo; Zeidan, Mouhammed; Raiyn, Jamal; Guccione, Salvatore; Rayan, Anwar

2014-01-01

The human histamine H4 receptor (hH4R), a member of the G-protein coupled receptors (GPCR) family, is an increasingly attractive drug target. It plays a key role in many cell pathways and many hH4R ligands are studied for the treatment of several inflammatory, allergic and autoimmune disorders, as well as for analgesic activity. Due to the challenging difficulties in the experimental elucidation of hH4R structure, virtual screening campaigns are normally run on homology based models. However, a wealth of information about the chemical properties of GPCR ligands has also accumulated over the last few years and an appropriate combination of these ligand-based knowledge with structure-based molecular modeling studies emerges as a promising strategy for computer-assisted drug design. Here, two chemoinformatics techniques, the Intelligent Learning Engine (ILE) and Iterative Stochastic Elimination (ISE) approach, were used to index chemicals for their hH4R bioactivity. An application of the prediction model on external test set composed of more than 160 hH4R antagonists picked from the chEMBL database gave enrichment factor of 16.4. A virtual high throughput screening on ZINC database was carried out, picking ∼ 4000 chemicals highly indexed as H4R antagonists' candidates. Next, a series of 3D models of hH4R were generated by molecular modeling and molecular dynamics simulations performed in fully atomistic lipid membranes. The efficacy of the hH4R 3D models in discrimination between actives and non-actives were checked and the 3D model with the best performance was chosen for further docking studies performed on the focused library. The output of these docking studies was a consensus library of 11 highly active scored drug candidates. Our findings suggest that a sequential combination of ligand-based chemoinformatics approaches with structure-based ones has the potential to improve the success rate in discovering new biologically active GPCR drugs and increase the enrichment factors in a synergistic manner.

Sketching the Invisible to Predict the Visible: From Drawing to Modeling in Chemistry.

PubMed

Cooper, Melanie M; Stieff, Mike; DeSutter, Dane

2017-10-01

Sketching as a scientific practice goes beyond the simple act of inscribing diagrams onto paper. Scientists produce a wide range of representations through sketching, as it is tightly coupled to model-based reasoning. Chemists in particular make extensive use of sketches to reason about chemical phenomena and to communicate their ideas. However, the chemical sciences have a unique problem in that chemists deal with the unseen world of the atomic-molecular level. Using sketches, chemists strive to develop causal mechanisms that emerge from the structure and behavior of molecular-level entities, to explain observations of the macroscopic visible world. Interpreting these representations and constructing sketches of molecular-level processes is a crucial component of student learning in the modern chemistry classroom. Sketches also serve as an important component of assessment in the chemistry classroom as student sketches give insight into developing mental models, which allows instructors to observe how students are thinking about a process. In this paper we discuss how sketching can be used to promote such model-based reasoning in chemistry and discuss two case studies of curricular projects, CLUE and The Connected Chemistry Curriculum, that have demonstrated a benefit of this approach. We show how sketching activities can be centrally integrated into classroom norms to promote model-based reasoning both with and without component visualizations. Importantly, each of these projects deploys sketching in support of other types of inquiry activities, such as making predictions or depicting models to support a claim; sketching is not an isolated activity but is used as a tool to support model-based reasoning in the discipline. Copyright © 2017 Cognitive Science Society, Inc.

Receptor Surface Models in the Classroom: Introducing Molecular Modeling to Students in a 3-D World

ERIC Educational Resources Information Center

Geldenhuys, Werner J.; Hayes, Michael; Van der Schyf, Cornelis J.; Allen, David D.; Malan, Sarel F.

2007-01-01

A simple, novel and generally applicable method to demonstrate structure-activity associations of a group of biologically interesting compounds in relation to receptor binding is described. This method is useful for undergraduates and graduate students in medicinal chemistry and computer modeling programs.

Designing an educative curriculum unit for teaching molecular geometry in high school chemistry

NASA Astrophysics Data System (ADS)

Makarious, Nader N.

Chemistry is a highly abstract discipline that is taught and learned with the aid of various models. Among the most challenging, yet a fundamental topic in general chemistry at the high school level, is molecular geometry. This study focused on developing exemplary educative curriculum materials pertaining to the topic of molecular geometry. The methodology used in this study consisted of several steps. First, a diverse set of models were analyzed to determine to what extent each model serves its purpose in teaching molecular geometry. Second, a number of high school teachers and college chemistry professors were asked to share their experiences on using models in teaching molecular geometry through an online questionnaire. Third, findings from the comparative analysis of models, teachers’ experiences, literature review on models and students’ misconceptions, the curriculum expectations of the Next Generation Science Standards and their emphasis on three-dimensional learning and nature of science (NOS) contributed to the development of the molecular geometry unit. Fourth, the developed unit was reviewed by fellow teachers and doctoral-level science education experts and was revised to further improve its coherence and clarity in support of teaching and learning of the molecular geometry concepts. The produced educative curriculum materials focus on the scientific practice of developing and using models as promoted in the Next Generations Science Standards (NGSS) while also addressing nature of science (NOS) goals. The educative features of the newly developed unit support teachers’ pedagogical knowledge (PK) and pedagogical content knowledge (PCK). The unit includes an overview, teacher’s guide, and eight detailed lesson plans with inquiry oriented modeling activities replete with models and suggestions for teachers, as well as formative and summative assessment tasks. The unit design process serves as a model for redesigning other instructional units in science disciplines in general and chemistry courses in particular.

Synthesis and CV Studies of Dithiol-terminated Metal Terpyridine Complexes

NASA Technical Reports Server (NTRS)

Asano, Sylvia; Fan, Wendy; Ng, Hou-Tee; Han, Jie; Meyyappan, M.

2003-01-01

Transition metal coordination complexes possess unique electronic structures that should be a good model for studying electronic transport behavior at a molecular level. The discrete, multiple redox states, low redox potential and the superb ability to establish contact with other molecular and electronic components by coordination chemistry have made this a subject of investigation for their possible application as active electronic components in molecular devices. We present the synthesis and electrochemical characterization of 4'-thioacetylphenyl-2'2:6',2"-terpyridine iron(II) complex and compare it with a model bis-terpyridine iron(II) complex by cyclic voltammetry. With the use of different working electrodes, the behavior of these complexes show different electron transfer rates.

Functional and structural characterization of the pentapeptide insertion of Theileria annulata lactate dehydrogenase by site-directed mutagenesis, comparative modeling and molecular dynamics simulations.

PubMed

Erdemir, Aysegul; Mutlu, Ozal

2017-06-01

Lactate dehydrogenase (LDH) is an important metabolic enzyme in glycolysis and it has been considered as the main energy source in many organisms including apicomplexan parasites. Differences at the active site loop of the host and parasite LDH's makes this enzyme an attractive target for drug inhibitors. In this study, five amino acid insertions in the active site pocket of Theileria annulata LDH (TaLDH) were deleted by PCR-based site-directed mutagenesis, expression and activity analysis of mutant and wild type TaLDH enzymes were performed. Removal of the insertion at the active site loop caused production of an inactive enzyme. Furthermore, structures of wild and mutant enzymes were predicted by comparative modeling and the importance of the insertions at the active site loop were also assigned by molecular docking and dynamics simulations in order to evaluate essential role of this loop for the enzymatic activity. Pentapeptide insertion removal resulted in loss of LDH activity due to deletion of Trp96 and conformational change of Arg98 because of loop instability. Analysis of wild type and mutant enzymes with comparative molecular dynamics simulations showed that the fluctuations of the loop residues increase in mutant enzyme. Together with in silico studies, in vitro results revealed that active site loop has a vital role in the enzyme activity and our findings promise hope for the further drug design studies against theileriosis and other apicomplexan parasite diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

Making Connections by Using Molecular Models in Geometry.

ERIC Educational Resources Information Center

Pacyga, Robert

1995-01-01

Describes two activities to analyze unit-cell structures from a geometric viewpoint and invites students to apply their mathematical understanding to scientific phenomena. Students form models of the simple cube, a building block of crystalline structures, and a methane molecule. (MKR)

An instructional design process based on expert knowledge for teaching students how mechanisms are explained.

PubMed

Trujillo, Caleb M; Anderson, Trevor R; Pelaez, Nancy J

2016-06-01

In biology and physiology courses, students face many difficulties when learning to explain mechanisms, a topic that is demanding due to the immense complexity and abstract nature of molecular and cellular mechanisms. To overcome these difficulties, we asked the following question: how does an instructor transform their understanding of biological mechanisms and other difficult-to-learn topics so that students can comprehend them? To address this question, we first reviewed a model of the components used by biologists to explain molecular and cellular mechanisms: the MACH model, with the components of methods (M), analogies (A), context (C), and how (H). Next, instructional materials were developed and the teaching activities were piloted with a physical MACH model. Students who used the MACH model to guide their explanations of mechanisms exhibited both improvements and some new difficulties. Third, a series of design-based research cycles was applied to bring the activities with an improved physical MACH model into biology and biochemistry courses. Finally, a useful rubric was developed to address prevalent student difficulties. Here, we present, for physiology and biology instructors, the knowledge and resources for explaining molecular and cellular mechanisms in undergraduate courses with an instructional design process aimed at realizing pedagogical content knowledge for teaching. Our four-stage process could be adapted to advance instruction with a range of models in the life sciences. Copyright © 2016 The American Physiological Society.

An instructional design process based on expert knowledge for teaching students how mechanisms are explained

PubMed Central

Anderson, Trevor R.; Pelaez, Nancy J.

2016-01-01

In biology and physiology courses, students face many difficulties when learning to explain mechanisms, a topic that is demanding due to the immense complexity and abstract nature of molecular and cellular mechanisms. To overcome these difficulties, we asked the following question: how does an instructor transform their understanding of biological mechanisms and other difficult-to-learn topics so that students can comprehend them? To address this question, we first reviewed a model of the components used by biologists to explain molecular and cellular mechanisms: the MACH model, with the components of methods (M), analogies (A), context (C), and how (H). Next, instructional materials were developed and the teaching activities were piloted with a physical MACH model. Students who used the MACH model to guide their explanations of mechanisms exhibited both improvements and some new difficulties. Third, a series of design-based research cycles was applied to bring the activities with an improved physical MACH model into biology and biochemistry courses. Finally, a useful rubric was developed to address prevalent student difficulties. Here, we present, for physiology and biology instructors, the knowledge and resources for explaining molecular and cellular mechanisms in undergraduate courses with an instructional design process aimed at realizing pedagogical content knowledge for teaching. Our four-stage process could be adapted to advance instruction with a range of models in the life sciences. PMID:27231262

Studies of New Fused Benzazepine as Selective Dopamine D3 Receptor Antagonists Using 3D-QSAR, Molecular Docking and Molecular Dynamics

PubMed Central

Liu, Jing; Li, Yan; Zhang, Shuwei; Xiao, Zhengtao; Ai, Chunzhi

2011-01-01

In recent years, great interest has been paid to the development of compounds with high selectivity for central dopamine (DA) D3 receptors, an interesting therapeutic target in the treatment of different neurological disorders. In the present work, based on a dataset of 110 collected benzazepine (BAZ) DA D3 antagonists with diverse kinds of structures, a variety of in silico modeling approaches, including comparative molecular field analysis (CoMFA), comparative similarity indices analysis (CoMSIA), homology modeling, molecular docking and molecular dynamics (MD) were carried out to reveal the requisite 3D structural features for activity. Our results show that both the receptor-based (Q2 = 0.603, R2ncv = 0.829, R2pre = 0.690, SEE = 0.316, SEP = 0.406) and ligand-based 3D-QSAR models (Q2 = 0.506, R2ncv =0.838, R2pre = 0.794, SEE = 0.316, SEP = 0.296) are reliable with proper predictive capacity. In addition, a combined analysis between the CoMFA, CoMSIA contour maps and MD results with a homology DA receptor model shows that: (1) ring-A, position-2 and R3 substituent in ring-D are crucial in the design of antagonists with higher activity; (2) more bulky R1 substituents (at position-2 of ring-A) of antagonists may well fit in the binding pocket; (3) hydrophobicity represented by MlogP is important for building satisfactory QSAR models; (4) key amino acids of the binding pocket are CYS101, ILE105, LEU106, VAL151, PHE175, PHE184, PRO254 and ALA251. To our best knowledge, this work is the first report on 3D-QSAR modeling of the new fused BAZs as DA D3 antagonists. These results might provide information for a better understanding of the mechanism of antagonism and thus be helpful in designing new potent DA D3 antagonists. PMID:21541053

Studies of new fused benzazepine as selective dopamine D3 receptor antagonists using 3D-QSAR, molecular docking and molecular dynamics.

PubMed

Liu, Jing; Li, Yan; Zhang, Shuwei; Xiao, Zhengtao; Ai, Chunzhi

2011-02-18

In recent years, great interest has been paid to the development of compounds with high selectivity for central dopamine (DA) D3 receptors, an interesting therapeutic target in the treatment of different neurological disorders. In the present work, based on a dataset of 110 collected benzazepine (BAZ) DA D3 antagonists with diverse kinds of structures, a variety of in silico modeling approaches, including comparative molecular field analysis (CoMFA), comparative similarity indices analysis (CoMSIA), homology modeling, molecular docking and molecular dynamics (MD) were carried out to reveal the requisite 3D structural features for activity. Our results show that both the receptor-based (Q(2) = 0.603, R(2) (ncv) = 0.829, R(2) (pre) = 0.690, SEE = 0.316, SEP = 0.406) and ligand-based 3D-QSAR models (Q(2) = 0.506, R(2) (ncv) =0.838, R(2) (pre) = 0.794, SEE = 0.316, SEP = 0.296) are reliable with proper predictive capacity. In addition, a combined analysis between the CoMFA, CoMSIA contour maps and MD results with a homology DA receptor model shows that: (1) ring-A, position-2 and R(3) substituent in ring-D are crucial in the design of antagonists with higher activity; (2) more bulky R(1) substituents (at position-2 of ring-A) of antagonists may well fit in the binding pocket; (3) hydrophobicity represented by MlogP is important for building satisfactory QSAR models; (4) key amino acids of the binding pocket are CYS101, ILE105, LEU106, VAL151, PHE175, PHE184, PRO254 and ALA251. To our best knowledge, this work is the first report on 3D-QSAR modeling of the new fused BAZs as DA D3 antagonists. These results might provide information for a better understanding of the mechanism of antagonism and thus be helpful in designing new potent DA D3 antagonists.

Molecular Descriptors

NASA Astrophysics Data System (ADS)

Consonni, Viviana; Todeschini, Roberto

In the last decades, several scientific researches have been focused on studying how to encompass and convert - by a theoretical pathway - the information encoded in the molecular structure into one or more numbers used to establish quantitative relationships between structures and properties, biological activities, or other experimental properties. Molecular descriptors are formally mathematical representations of a molecule obtained by a well-specified algorithm applied to a defined molecular representation or a well-specified experimental procedure. They play a fundamental role in chemistry, pharmaceutical sciences, environmental protection policy, toxicology, ecotoxicology, health research, and quality control. Evidence of the interest of the scientific community in the molecular descriptors is provided by the huge number of descriptors proposed up today: more than 5000 descriptors derived from different theories and approaches are defined in the literature and most of them can be calculated by means of dedicated software applications. Molecular descriptors are of outstanding importance in the research fields of quantitative structure-activity relationships (QSARs) and quantitative structure-property relationships (QSPRs), where they are the independent chemical information used to predict the properties of interest. Along with the definition of appropriate molecular descriptors, the molecular structure representation and the mathematical tools for deriving and assessing models are other fundamental components of the QSAR/QSPR approach. The remarkable progress during the last few years in chemometrics and chemoinformatics has led to new strategies for finding mathematical meaningful relationships between the molecular structure and biological activities, physico-chemical, toxicological, and environmental properties of chemicals. Different approaches for deriving molecular descriptors here reviewed and some of the most relevant descriptors are presented in detail with numerical examples.

Bleomycin induces molecular changes directly relevant to idiopathic pulmonary fibrosis: a model for "active" disease.

PubMed

Peng, Ruoqi; Sridhar, Sriram; Tyagi, Gaurav; Phillips, Jonathan E; Garrido, Rosario; Harris, Paul; Burns, Lisa; Renteria, Lorena; Woods, John; Chen, Leena; Allard, John; Ravindran, Palanikumar; Bitter, Hans; Liang, Zhenmin; Hogaboam, Cory M; Kitson, Chris; Budd, David C; Fine, Jay S; Bauer, Carla M T; Stevenson, Christopher S

2013-01-01

The preclinical model of bleomycin-induced lung fibrosis, used to investigate mechanisms related to idiopathic pulmonary fibrosis (IPF), has incorrectly predicted efficacy for several candidate compounds suggesting that it may be of limited value. As an attempt to improve the predictive nature of this model, integrative bioinformatic approaches were used to compare molecular alterations in the lungs of bleomycin-treated mice and patients with IPF. Using gene set enrichment analysis we show for the first time that genes differentially expressed during the fibrotic phase of the single challenge bleomycin model were significantly enriched in the expression profiles of IPF patients. The genes that contributed most to the enrichment were largely involved in mitosis, growth factor, and matrix signaling. Interestingly, these same mitotic processes were increased in the expression profiles of fibroblasts isolated from rapidly progressing, but not slowly progressing, IPF patients relative to control subjects. The data also indicated that TGFβ was not the sole mediator responsible for the changes observed in this model since the ALK-5 inhibitor SB525334 effectively attenuated some but not all of the fibrosis associated with this model. Although some would suggest that repetitive bleomycin injuries may more effectively model IPF-like changes, our data do not support this conclusion. Together, these data highlight that a single bleomycin instillation effectively replicates several of the specific pathogenic molecular changes associated with IPF, and may be best used as a model for patients with active disease.

Statistical molecular design of balanced compound libraries for QSAR modeling.

PubMed

Linusson, A; Elofsson, M; Andersson, I E; Dahlgren, M K

2010-01-01

A fundamental step in preclinical drug development is the computation of quantitative structure-activity relationship (QSAR) models, i.e. models that link chemical features of compounds with activities towards a target macromolecule associated with the initiation or progression of a disease. QSAR models are computed by combining information on the physicochemical and structural features of a library of congeneric compounds, typically assembled from two or more building blocks, and biological data from one or more in vitro assays. Since the models provide information on features affecting the compounds' biological activity they can be used as guides for further optimization. However, in order for a QSAR model to be relevant to the targeted disease, and drug development in general, the compound library used must contain molecules with balanced variation of the features spanning the chemical space believed to be important for interaction with the biological target. In addition, the assays used must be robust and deliver high quality data that are directly related to the function of the biological target and the associated disease state. In this review, we discuss and exemplify the concept of statistical molecular design (SMD) in the selection of building blocks and final synthetic targets (i.e. compounds to synthesize) to generate information-rich, balanced libraries for biological testing and computation of QSAR models.

A minimal titration model of the mammalian dynamical heat shock response

NASA Astrophysics Data System (ADS)

Sivéry, Aude; Courtade, Emmanuel; Thommen, Quentin

2016-12-01

Environmental stress, such as oxidative or heat stress, induces the activation of the heat shock response (HSR) and leads to an increase in the heat shock proteins (HSPs) level. These HSPs act as molecular chaperones to maintain cellular proteostasis. Controlled by highly intricate regulatory mechanisms, having stress-induced activation and feedback regulations with multiple partners, the HSR is still incompletely understood. In this context, we propose a minimal molecular model for the gene regulatory network of the HSR that reproduces quantitatively different heat shock experiments both on heat shock factor 1 (HSF1) and HSPs activities. This model, which is based on chemical kinetics laws, is kept with a low dimensionality without altering the biological interpretation of the model dynamics. This simplistic model highlights the titration of HSF1 by chaperones as the guiding line of the network. Moreover, by a steady states analysis of the network, three different temperature stress regimes appear: normal, acute, and chronic, where normal stress corresponds to pseudo thermal adaption. The protein triage that governs the fate of damaged proteins or the different stress regimes are consequences of the titration mechanism. The simplicity of the present model is of interest in order to study detailed modelling of cross regulation between the HSR and other major genetic networks like the cell cycle or the circadian clock.

Binding Mode Analyses and Pharmacophore Model Development for Stilbene Derivatives as a Novel and Competitive Class of α-Glucosidase Inhibitors

PubMed Central

Kim, Jun Young; Arooj, Mahreen; Kim, Siu; Hwang, Swan; Kim, Byeong-Woo; Park, Ki Hun; Lee, Keun Woo

2014-01-01

Stilbene urea derivatives as a novel and competitive class of non-glycosidic α-glucosidase inhibitors are effective for the treatment of type II diabetes and obesity. The main purposes of our molecular modeling study are to explore the most suitable binding poses of stilbene derivatives with analyzing the binding affinity differences and finally to develop a pharmacophore model which would represents critical features responsible for α-glucosidase inhibitory activity. Three-dimensional structure of S. cerevisiae α-glucosidase was built by homology modeling method and the structure was used for the molecular docking study to find out the initial binding mode of compound 12, which is the most highly active one. The initial structure was subjected to molecular dynamics (MD) simulations for protein structure adjustment at compound 12-bound state. Based on the adjusted conformation, the more reasonable binding modes of the stilbene urea derivatives were obtained from molecular docking and MD simulations. The binding mode of the derivatives was validated by correlation analysis between experimental Ki value and interaction energy. Our results revealed that the binding modes of the potent inhibitors were engaged with important hydrogen bond, hydrophobic, and π-interactions. With the validated compound 12-bound structure obtained from combining approach of docking and MD simulation, a proper four featured pharmacophore model was generated. It was also validated by comparison of fit values with the Ki values. Thus, these results will be helpful for understanding the relationship between binding mode and bioactivity and for designing better inhibitors from stilbene derivatives. PMID:24465730

Discrete Fourier Transform-Based Multivariate Image Analysis: Application to Modeling of Aromatase Inhibitory Activity.

PubMed

Barigye, Stephen J; Freitas, Matheus P; Ausina, Priscila; Zancan, Patricia; Sola-Penna, Mauro; Castillo-Garit, Juan A

2018-02-12

We recently generalized the formerly alignment-dependent multivariate image analysis applied to quantitative structure-activity relationships (MIA-QSAR) method through the application of the discrete Fourier transform (DFT), allowing for its application to noncongruent and structurally diverse chemical compound data sets. Here we report the first practical application of this method in the screening of molecular entities of therapeutic interest, with human aromatase inhibitory activity as the case study. We developed an ensemble classification model based on the two-dimensional (2D) DFT MIA-QSAR descriptors, with which we screened the NCI Diversity Set V (1593 compounds) and obtained 34 chemical compounds with possible aromatase inhibitory activity. These compounds were docked into the aromatase active site, and the 10 most promising compounds were selected for in vitro experimental validation. Of these compounds, 7419 (nonsteroidal) and 89 201 (steroidal) demonstrated satisfactory antiproliferative and aromatase inhibitory activities. The obtained results suggest that the 2D-DFT MIA-QSAR method may be useful in ligand-based virtual screening of new molecular entities of therapeutic utility.

Design of novel quinazolinone derivatives as inhibitors for 5HT7 receptor.

PubMed

Chitta, Aparna; Jatavath, Mohan Babu; Fatima, Sabiha; Manga, Vijjulatha

2012-02-01

To study the pharmacophore properties of quinazolinone derivatives as 5HT(7) inhibitors, 3D QSAR methodologies, namely Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) were applied, partial least square (PLS) analysis was performed and QSAR models were generated. The derived model showed good statistical reliability in terms of predicting the 5HT(7) inhibitory activity of the quinazolione derivative, based on molecular property fields like steric, electrostatic, hydrophobic, hydrogen bond donor and hydrogen bond acceptor fields. This is evident from statistical parameters like q(2) (cross validated correlation coefficient) of 0.642, 0.602 and r(2) (conventional correlation coefficient) of 0.937, 0.908 for CoMFA and CoMSIA respectively. The predictive ability of the models to determine 5HT(7) antagonistic activity is validated using a test set of 26 molecules that were not included in the training set and the predictive r(2) obtained for the test set was 0.512 & 0.541. Further, the results of the derived model are illustrated by means of contour maps, which give an insight into the interaction of the drug with the receptor. The molecular fields so obtained served as the basis for the design of twenty new ligands. In addition, ADME (Adsorption, Distribution, Metabolism and Elimination) have been calculated in order to predict the relevant pharmaceutical properties, and the results are in conformity with required drug like properties.

Virtual screening and optimization of Type II inhibitors of JAK2 from a natural product library.

PubMed

Ma, Dik-Lung; Chan, Daniel Shiu-Hin; Wei, Guo; Zhong, Hai-Jing; Yang, Hui; Leung, Lai To; Gullen, Elizabeth A; Chiu, Pauline; Cheng, Yung-Chi; Leung, Chung-Hang

2014-11-21

Amentoflavone has been identified as a JAK2 inhibitor by structure-based virtual screening of a natural product library. In silico optimization using the DOLPHIN model yielded analogues with enhanced potency against JAK2 activity and HCV activity in cellulo. Molecular modeling and kinetic experiments suggested that the analogues may function as Type II inhibitors of JAK2.

Antimalarial activity of synthetic 1,2,4-trioxanes and cyclic peroxy ketals, a quantum similarity study

NASA Astrophysics Data System (ADS)

Gironés, X.; Gallegos, A.; Carbó-Dorca, R.

2001-12-01

In this work, the antimalarial activity of two series of 20 and 7 synthetic 1,2,4-trioxanes and a set of 20 cyclic peroxy ketals are tested for correlation search by means of Molecular Quantum Similarity Measures (MQSM). QSAR models, dealing with different biological responses (IC90, IC50 and ED90) of the parasite Plasmodium Falciparum, are constructed using MQSM as molecular descriptors and are satisfactorily correlated. The statistical results of the 20 1,2,4-trioxanes are deeply analyzed to elucidate the relevant structural features in the biological activity, revealing the importance of phenyl substitutions.

New insights into heat induced structural changes of pectin methylesterase on fluorescence spectroscopy and molecular modeling basis

NASA Astrophysics Data System (ADS)

Nistor, Oana Viorela; Stănciuc, Nicoleta; Aprodu, Iuliana; Botez, Elisabeta

2014-07-01

Heat-induced structural changes of Aspergillus oryzae pectin methylesterase (PME) were studied by means of fluorescence spectroscopy and molecular modeling, whereas the functional enzyme stability was monitored by inactivation studies. The fluorescence spectroscopy experiments were performed at two pH value (4.5 and 7.0). At both pH values, the phase diagrams were linear, indicating the presence of two molecular species induced by thermal treatment. A red shift of 7 nm was observed at neutral pH by increasing temperature up to 60 °C, followed by a blue shift of 4 nm at 70 °C, suggesting significant conformational rearrangements. The quenching experiments using acrylamide and iodide demonstrate a more flexible conformation of enzyme with increasing temperature, especially at neutral pH. The experimental results were complemented with atomic level observations on PME model behavior after performing molecular dynamics simulations at different temperatures. The inactivation kinetics of PME in buffer solutions was fitted using a first-order kinetics model, resulting in activation energy of 241.4 ± 7.51 kJ mol-1.

Three-dimensional quantitative structure-activity relationship CoMSIA/CoMFA and LeapFrog studies on novel series of bicyclo [4.1.0] heptanes derivatives as melanin-concentrating hormone receptor R1 antagonists.

PubMed

Morales-Bayuelo, Alejandro; Ayazo, Hernan; Vivas-Reyes, Ricardo

2010-10-01

Comparative molecular similarity indices analysis (CoMSIA) and comparative molecular field analysis (CoMFA) were performed on a series of bicyclo [4.1.0] heptanes derivatives as melanin-concentrating hormone receptor R1 antagonists (MCHR1 antagonists). Molecular superimposition of antagonists on the template structure was performed by database alignment method. The statistically significant model was established on sixty five molecules, which were validated by a test set of ten molecules. The CoMSIA model yielded the best predictive model with a q(2) = 0.639, non cross-validated R(2) of 0.953, F value of 92.802, bootstrapped R(2) of 0.971, standard error of prediction = 0.402, and standard error of estimate = 0.146 while the CoMFA model yielded a q(2) = 0.680, non cross-validated R(2) of 0.922, F value of 114.351, bootstrapped R(2) of 0.925, standard error of prediction = 0.364, and standard error of estimate = 0.180. CoMFA analysis maps were employed for generating a pseudo cavity for LeapFrog calculation. The contour maps obtained from 3D-QSAR studies were appraised for activity trends for the molecules analyzed. The results show the variability of steric and electrostatic contributions that determine the activity of the MCHR1 antagonist, with these results we proposed new antagonists that may be more potent than previously reported, these novel antagonists were designed from the addition of highly electronegative groups in the substituent di(i-C(3)H(7))N- of the bicycle [4.1.0] heptanes, using the model CoMFA which also was used for the molecular design using the technique LeapFrog. The data generated from the present study will further help to design novel, potent, and selective MCHR1 antagonists. Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.

Modeling of the Reaction Mechanism of Enzymatic Radical C–C Coupling by Benzylsuccinate Synthase

PubMed Central

Szaleniec, Maciej; Heider, Johann

2016-01-01

Molecular modeling techniques and density functional theory calculations were performed to study the mechanism of enzymatic radical C–C coupling catalyzed by benzylsuccinate synthase (BSS). BSS has been identified as a glycyl radical enzyme that catalyzes the enantiospecific fumarate addition to toluene initiating its anaerobic metabolism in the denitrifying bacterium Thauera aromatica, and this reaction represents the general mechanism of toluene degradation in all known anaerobic degraders. In this work docking calculations, classical molecular dynamics (MD) simulations, and DFT+D2 cluster modeling was employed to address the following questions: (i) What mechanistic details of the BSS reaction yield the most probable molecular model? (ii) What is the molecular basis of enantiospecificity of BSS? (iii) Is the proposed mechanism consistent with experimental observations, such as an inversion of the stereochemistry of the benzylic protons, syn addition of toluene to fumarate, exclusive production of (R)-benzylsuccinate as a product and a kinetic isotope effect (KIE) ranging between 2 and 4? The quantum mechanics (QM) modeling confirms that the previously proposed hypothetical mechanism is the most probable among several variants considered, although C–H activation and not C–C coupling turns out to be the rate limiting step. The enantiospecificity of the enzyme seems to be enforced by a thermodynamic preference for binding of fumarate in the pro(R) orientation and reverse preference of benzyl radical attack on fumarate in pro(S) pathway which results with prohibitively high energy barrier of the radical quenching. Finally, the proposed mechanism agrees with most of the experimental observations, although the calculated intrinsic KIE from the model (6.5) is still higher than the experimentally observed values (4.0) which suggests that both C–H activation and radical quenching may jointly be involved in the kinetic control of the reaction. PMID:27070573

Preclinical Magnetic Resonance Imaging and Spectroscopy Studies of Memory, Aging, and Cognitive Decline

PubMed Central

Febo, Marcelo; Foster, Thomas C.

2016-01-01

Neuroimaging provides for non-invasive evaluation of brain structure and activity and has been employed to suggest possible mechanisms for cognitive aging in humans. However, these imaging procedures have limits in terms of defining cellular and molecular mechanisms. In contrast, investigations of cognitive aging in animal models have mostly utilized techniques that have offered insight on synaptic, cellular, genetic, and epigenetic mechanisms affecting memory. Studies employing magnetic resonance imaging and spectroscopy (MRI and MRS, respectively) in animal models have emerged as an integrative set of techniques bridging localized cellular/molecular phenomenon and broader in vivo neural network alterations. MRI methods are remarkably suited to longitudinal tracking of cognitive function over extended periods permitting examination of the trajectory of structural or activity related changes. Combined with molecular and electrophysiological tools to selectively drive activity within specific brain regions, recent studies have begun to unlock the meaning of fMRI signals in terms of the role of neural plasticity and types of neural activity that generate the signals. The techniques provide a unique opportunity to causally determine how memory-relevant synaptic activity is processed and how memories may be distributed or reconsolidated over time. The present review summarizes research employing animal MRI and MRS in the study of brain function, structure, and biochemistry, with a particular focus on age-related cognitive decline. PMID:27468264

Molecular docking and dynamics simulation analyses unraveling the differential enzymatic catalysis by plant and fungal laccases with respect to lignin biosynthesis and degradation.

PubMed

Awasthi, Manika; Jaiswal, Nivedita; Singh, Swati; Pandey, Veda P; Dwivedi, Upendra N

2015-09-01

Laccase, widely distributed in bacteria, fungi, and plants, catalyzes the oxidation of wide range of compounds. With regards to one of the important physiological functions, plant laccases are considered to catalyze lignin biosynthesis while fungal laccases are considered for lignin degradation. The present study was undertaken to explain this dual function of laccases using in-silico molecular docking and dynamics simulation approaches. Modeling and superimposition analyses of one each representative of plant and fungal laccases, namely, Populus trichocarpa and Trametes versicolor, respectively, revealed low level of similarity in the folding of two laccases at 3D levels. Docking analyses revealed significantly higher binding efficiency for lignin model compounds, in proportion to their size, for fungal laccase as compared to that of plant laccase. Residues interacting with the model compounds at the respective enzyme active sites were found to be in conformity with their role in lignin biosynthesis and degradation. Molecular dynamics simulation analyses for the stability of docked complexes of plant and fungal laccases with lignin model compounds revealed that tetrameric lignin model compound remains attached to the active site of fungal laccase throughout the simulation period, while it protrudes outwards from the active site of plant laccase. Stability of these complexes was further analyzed on the basis of binding energy which revealed significantly higher stability of fungal laccase with tetrameric compound than that of plant. The overall data suggested a situation favorable for the degradation of lignin polymer by fungal laccase while its synthesis by plant laccase.

Molecular dynamics simulations on the inhibition of cyclin-dependent kinases 2 and 5 in the presence of activators.

PubMed

Zhang, Bing; Tan, Vincent B C; Lim, Kian Meng; Tay, Tong Earn

2006-06-01

Interests in CDK2 and CDK5 have stemmed mainly from their association with cancer and neuronal migration or differentiation related diseases and the need to design selective inhibitors for these kinases. Molecular dynamics (MD) simulations have not only become a viable approach to drug design because of advances in computer technology but are increasingly an integral part of drug discovery processes. It is common in MD simulations of inhibitor/CDK complexes to exclude the activator of the CDKs in the structural models to keep computational time tractable. In this paper, we present simulation results of CDK2 and CDK5 with roscovitine using models with and without their activators (cyclinA and p25). While p25 was found to induce slight changes in CDK5, the calculations support that cyclinA leads to significant conformational changes near the active site of CDK2. This suggests that detailed and structure-based inhibitor design targeted at these CDKs should employ activator-included models of the kinases. Comparisons between P/CDK2/cyclinA/roscovitine and CDK5/p25/roscovitine complexes reveal differences in the conformations of the glutamine around the active sites, which may be exploited to find highly selective inhibitors with respect to CDK2 and CDK5.

Quantitative structure-activity relationships of selective antagonists of glucagon receptor using QuaSAR descriptors.

PubMed

Manoj Kumar, Palanivelu; Karthikeyan, Chandrabose; Hari Narayana Moorthy, Narayana Subbiah; Trivedi, Piyush

2006-11-01

In the present paper, quantitative structure activity relationship (QSAR) approach was applied to understand the affinity and selectivity of a novel series of triaryl imidazole derivatives towards glucagon receptor. Statistically significant and highly predictive QSARs were derived for glucagon receptor inhibition by triaryl imidazoles using QuaSAR descriptors of molecular operating environment (MOE) employing computer-assisted multiple regression procedure. The generated QSAR models revealed that factors related to hydrophobicity, molecular shape and geometry predominantly influences glucagon receptor binding affinity of the triaryl imidazoles indicating the relevance of shape specific steric interactions between the molecule and the receptor. Further, QSAR models formulated for selective inhibition of glucagon receptor over p38 mitogen activated protein (MAP) kinase of the compounds in the series highlights that the same structural features, which influence the glucagon receptor affinity, also contribute to their selective inhibition.

New modulated design and synthesis of quercetin-Cu(II)/Zn(II)-Sn2(IV) scaffold as anticancer agents: in vitro DNA binding profile, DNA cleavage pathway and Topo-I activity.

PubMed

Tabassum, Sartaj; Zaki, Mehvash; Afzal, Mohd; Arjmand, Farukh

2013-07-21

New molecular topologies quercetin-Cu(II)-Sn2(IV) and Zn(II)-Sn2(IV)1 and 2 were designed and synthesized to act as potential cancer chemotherapeutic agents. Their interaction with CT DNA by UV-vis and fluorescence spectroscopy was evaluated revealing an electrostatic mode of binding. Quercetin complexes are capable of promoting DNA cleavage involving both single and double strand breaks. Complex 1 cleaved pBR322 DNA via an oxidative mechanism while 2 followed a hydrolytic pathway, accessible to the minor groove of the DNA double helix in accordance with molecular docking studies with the DNA duplex of sequence d(CGCGAATTCGCG)2 dodecamer demonstrating that the complex was stabilized by additional electrostatic and hydrogen bonding interactions with the DNA. ROS such as OH˙, H2O2 and O2˙(-) are the major metabolites responsible for chronic diseases such as cancer, respiratory disorders, HIV, and diabetes etc., therefore eliminating ROS by molecular scaffolds involving SOD enzymatic activity has emerged as a potential way to develop a novel class of drugs. Therefore, in vitro superoxide dismutase activity of redox active complex 1 was evaluated by using a xanthine/xanthine oxidase-NBT assay which showed an IC50 value of 2.26 μM. Moreover, the cytotoxicity of both the complexes were screened on a panel of human carcinoma cell lines (GI50 values <8.7 μM) which revealed that 1 has a better prospect of acting as a cancer chemotherapeutic agent, and to elucidate the mechanism of tumor inhibition, Topo-I enzymatic activity was carried out. Furthermore, molecular modeling studies were carried out to understand molecular features important for drug-enzyme interactions which offer new insights into the experimental model observations.

CALCULATING PHYSICAL PROPERTIES OF ORGANIC COMPOUNDS FOR ENVIRONMENTAL MODELING FROM MOLECULAR STRUCTURE

EPA Science Inventory

Mathematical models for predicting the transport and fate of pollutants in the environment require reactivity parameter values-- that is value of the physical and chemical constants that govern reactivity. Although empirical structure activity relationships have been developed t...

Introducing Basic Molecular Biology to Turkish Rural and Urban Primary School Children via Hands-on PCR and Gel Electrophoresis Activities

ERIC Educational Resources Information Center

Selli, Cigdem; Yildirim, Gokce; Kaymak, Aysegul; Karacicek, Bilge; Ogut, Deniz; Gungor, Turkan; Erem, Erdem; Ege, Mehmet; Bümen, Nilay; Tosun, Metiner

2014-01-01

This study includes the results of a 2-day education project titled "Molecular Biology Laboratory Summer School, MoBiLYO." The project was held at a University Research Center by scientists from Department of Pharmacology and graduate students. The project was composed of introductory lectures, model construction, DNA isolation,…

Design, synthesis and molecular simulation studies of dihydrostilbene derivatives as potent tyrosinase inhibitors.

PubMed

Vontzalidou, Argyro; Zoidis, Grigoris; Chaita, Eliza; Makropoulou, Maria; Aligiannis, Nektarios; Lambrinidis, George; Mikros, Emmanuel; Skaltsounis, Alexios-Leandros

2012-09-01

The synthesis, molecular modeling and biological evaluation of substituted deoxybenzoins and optimized dihydrostilbenes are reported. Preliminary structure-activity relationship data were elucidated and lead compounds suitable for further optimization were discovered. Dihydrostilbene 7 is a particularly potent inhibitor (IC(50)=8.44 μM, more potent than kojic acid). Copyright © 2012 Elsevier Ltd. All rights reserved.

Density functional theory molecular modeling and antimicrobial behaviour of selected 1,2,3,4,5,6,7,8-octahydroacridine-N(10)-oxides

NASA Astrophysics Data System (ADS)

Marinescu, Maria; Cinteza, Ludmila Otilia; Marton, George Iuliu; Marutescu, Luminita Gabriela; Chifiriuc, Mariana-Carmen; Constantinescu, Catalin

2017-09-01

A series of 9-substituted 1,2,3,4,5,6,7,8-octahydroacridine-N(10)-oxides is evaluated against 12 bacterial and fungal strains, for their microbicidal and anti-pathogenic features. The largest spectrum of the antibacterial activity is evidenced for the nitro- (2b) and hydroxy- (5b) N-oxides, followed by the amino-N-oxide (3b). Density functional theory (DFT) modeling of the molecular structure and frontier molecular orbitals, i.e. highest occupied/lowest unoccupied molecular orbital (HOMO/LUMO), is accomplished by using the GAMESS 2012 software at M11/ktzvp level of theory in order to find their structural and electronic parameters. We show that the planarity of the molecules and the presence of the electron withdrawing group are advantages for its antimicrobial activity. Finally, we briefly present and discuss results on the processing of such compounds into thin films and hybrid structures by laser-assisted techniques, i.e. matrix-assisted pulsed laser evaporation (MAPLE) or laser-induced forward transfer (LIFT), to provide simple and environmental friendly, state-of-the-art solutions for antimicrobial/medical coatings and devices.

μ Opioid receptor: novel antagonists and structural modeling

NASA Astrophysics Data System (ADS)

Kaserer, Teresa; Lantero, Aquilino; Schmidhammer, Helmut; Spetea, Mariana; Schuster, Daniela

2016-02-01

The μ opioid receptor (MOR) is a prominent member of the G protein-coupled receptor family and the molecular target of morphine and other opioid drugs. Despite the long tradition of MOR-targeting drugs, still little is known about the ligand-receptor interactions and structure-function relationships underlying the distinct biological effects upon receptor activation or inhibition. With the resolved crystal structure of the β-funaltrexamine-MOR complex, we aimed at the discovery of novel agonists and antagonists using virtual screening tools, i.e. docking, pharmacophore- and shape-based modeling. We suggest important molecular interactions, which active molecules share and distinguish agonists and antagonists. These results allowed for the generation of theoretically validated in silico workflows that were employed for prospective virtual screening. Out of 18 virtual hits evaluated in in vitro pharmacological assays, three displayed antagonist activity and the most active compound significantly inhibited morphine-induced antinociception. The new identified chemotypes hold promise for further development into neurochemical tools for studying the MOR or as potential therapeutic lead candidates.

Molecular dynamics exploration of poration and leaking caused by Kalata B1 in HIV-infected cell membrane compared to host and HIV membranes.

PubMed

Nawae, Wanapinun; Hannongbua, Supa; Ruengjitchatchawalya, Marasri

2017-06-15

The membrane disruption activities of kalata B1 (kB1) were investigated using molecular dynamics simulations with membrane models. The models were constructed to mimic the lipid microdomain formation in membranes of HIV particle, HIV-infected cell, and host cell. The differences in the lipid ratios of these membranes caused the formation of liquid ordered (lo) domains of different sizes, which affected the binding and activity of kB1. Stronger kB1 disruptive activity was observed for the membrane with small sized lo domain. Our results show that kB1 causes membrane leaking without bilayer penetration. The membrane poration mechanism involved in the disorganization of the lo domain and in cholesterol inter-leaflet translocation is described. This study enhances our understanding of the membrane activity of kB1, which may be useful for designing novel and potentially therapeutic peptides based on the kB1 framework.

Triaryl Benzimidazoles as a New Class of Antibacterial Agents against Resistant Pathogenic Microorganisms.

PubMed

Picconi, Pietro; Hind, Charlotte; Jamshidi, Shirin; Nahar, Kazi; Clifford, Melanie; Wand, Matthew E; Sutton, J Mark; Rahman, Khondaker Miraz

2017-07-27

A new class of nontoxic triaryl benzimidazole compounds, derived from existing classes of DNA minor groove binders, were designed, synthesized, and evaluated for their antibacterial activity against multidrug resistant (MDR) Gram-positive and Gram-negative species. Molecular modeling experiments suggest that the newly synthesized class cannot be accommodated within the minor groove of DNA due to a change in the shape of the molecules. Compounds 8, 13, and 14 were found to be the most active of the series, with MICs in the range of 0.5-4 μg/mL against the MDR Staphylococci and Enterococci species. Compound 13 showed moderate activity against the MDR Gram-negative strains, with MICs in the range of 16-32 μg/mL. Active compounds showed a bactericidal mode of action, and a mechanistic study suggested the inhibition of bacterial gyrase as the mechanism of action (MOA) of this chemical class. The MOA was further supported by the molecular modeling study.

Molecular docking, 3D-QSAR and structural optimization on imidazo-pyridine derivatives dually targeting AT1 and PPARγ

PubMed Central

Zhang, Jun; Hao, Qing-Qing; Liu, Xin; Jing, Zhi; Jia, Wen-Qing; Wang, Shu-Qing; Xu, Wei-Ren; Cheng, Xian-Chao; Wang, Run-Ling

2017-01-01

Telmisartan, a bifunctional agent of blood pressure lowering and glycemia reduction, was previously reported to antagonize angiotensin II type 1 (AT1) receptor and partially activate peroxisome proliferator-activated receptor γ (PPARγ) simultaneously. Through the modification to telmisartan, researchers designed and obtained imidazo-\\pyridine derivatives with the IC50s of 0.49∼94.1 nM against AT1 and EC50s of 20∼3640 nM towards PPARγ partial activation. For minutely inquiring the interaction modes with the relevant receptor and analyzing the structure-activity relationships, molecular docking and 3D-QSAR (Quantitative structure-activity relationships) analysis of these imidazo-\\pyridines on dual targets were conducted in this work. Docking approaches of these derivatives with both receptors provided explicit interaction behaviors and excellent matching degree with the binding pockets. The best CoMFA (Comparative Molecular Field Analysis) models exhibited predictive results of q2=0.553, r2=0.954, SEE=0.127, r2pred=0.779 for AT1 and q2=0.503, r2=1.00, SEE=0.019, r2pred=0.604 for PPARγ, respectively. The contour maps from the optimal model showed detailed information of structural features (steric and electrostatic fields) towards the biological activity. Combining the bioisosterism with the valuable information from above studies, we designed six molecules with better predicted activities towards AT1 and PPARγ partial activation. Overall, these results could be useful for designing potential dual AT1 antagonists and partial PPARγ agonists. PMID:28445965

Molecular docking, 3D-QSAR and structural optimization on imidazo-pyridine derivatives dually targeting AT1 and PPARg.

PubMed

Zhang, Jun; Hao, Qing-Qing; Liu, Xin; Jing, Zhi; Jia, Wen-Qing; Wang, Shu-Qing; Xu, Wei-Ren; Cheng, Xian-Chao; Wang, Run-Ling

2017-04-11

Telmisartan, a bifunctional agent of blood pressure lowering and glycemia reduction, was previously reported to antagonize angiotensin II type 1 (AT1) receptor and partially activate peroxisome proliferator-activated receptor γ (PPARγ) simultaneously. Through the modification to telmisartan, researchers designed and obtained imidazo-\\pyridine derivatives with the IC50s of 0.49~94.1 nM against AT1 and EC50s of 20~3640 nM towards PPARγ partial activation. For minutely inquiring the interaction modes with the relevant receptor and analyzing the structure-activity relationships, molecular docking and 3D-QSAR (Quantitative structure-activity relationships) analysis of these imidazo-\\pyridines on dual targets were conducted in this work. Docking approaches of these derivatives with both receptors provided explicit interaction behaviors and excellent matching degree with the binding pockets. The best CoMFA (Comparative Molecular Field Analysis) models exhibited predictive results of q2=0.553, r2=0.954, SEE=0.127, r2pred=0.779 for AT1 and q2=0.503, r2=1.00, SEE=0.019, r2pred=0.604 for PPARγ, respectively. The contour maps from the optimal model showed detailed information of structural features (steric and electrostatic fields) towards the biological activity. Combining the bioisosterism with the valuable information from above studies, we designed six molecules with better predicted activities towards AT1 and PPARγ partial activation. Overall, these results could be useful for designing potential dual AT1 antagonists and partial PPARγ agonists.

Multiple templates-based homology modeling enhances structure quality of AT1 receptor: validation by molecular dynamics and antagonist docking.

PubMed

Sokkar, Pandian; Mohandass, Shylajanaciyar; Ramachandran, Murugesan

2011-07-01

We present a comparative account on 3D-structures of human type-1 receptor (AT1) for angiotensin II (AngII), modeled using three different methodologies. AngII activates a wide spectrum of signaling responses via the AT1 receptor that mediates physiological control of blood pressure and diverse pathological actions in cardiovascular, renal, and other cell types. Availability of 3D-model of AT1 receptor would significantly enhance the development of new drugs for cardiovascular diseases. However, templates of AT1 receptor with low sequence similarity increase the complexity in straightforward homology modeling, and hence there is a need to evaluate different modeling methodologies in order to use the models for sensitive applications such as rational drug design. Three models were generated for AT1 receptor by, (1) homology modeling with bovine rhodopsin as template, (2) homology modeling with multiple templates and (3) threading using I-TASSER web server. Molecular dynamics (MD) simulation (15 ns) of models in explicit membrane-water system, Ramachandran plot analysis and molecular docking with antagonists led to the conclusion that multiple template-based homology modeling outweighs other methodologies for AT1 modeling.

Derivatives of Ergot-alkaloids: Molecular structure, physical properties, and structure-activity relationships

NASA Astrophysics Data System (ADS)

Ivanova, Bojidarka B.; Spiteller, Michael

2012-09-01

A comprehensive screening of fifteen functionalized Ergot-alkaloids, containing bulk aliphatic cyclic substituents at D-ring of the ergoline molecular skeleton was performed, studying their structure-active relationships and model interactions with α2A-adreno-, serotonin (5HT2A) and dopamine D3 (D3A) receptors. The accounted high affinity to the receptors binding loops and unusual bonding situations, joined with the molecular flexibility of the substituents and the presence of proton accepting/donating functional groups in the studied alkaloids, may contribute to further understanding the mechanisms of biological activity in vivo and in predicting their therapeutic potential in central nervous system (CNS), including those related the Schizophrenia. Since the presented correlation between the molecular structure and properties, was based on the comprehensively theoretical computational and experimental physical study on the successfully isolated derivatives, through using routine synthetic pathways in a relatively high yields, marked these derivatives as 'treasure' for further experimental and theoretical studied in areas such as: (a) pharmacological and clinical testing; (b) molecular-drugs design of novel psychoactive substances; (c) development of the analytical protocols for determination of Ergot-alkaloids through a functionalization of the ergoline-skeleton, and more.

Memory Synapses Are Defined by Distinct Molecular Complexes: A Proposal

PubMed Central

Sossin, Wayne S.

2018-01-01

Synapses are diverse in form and function. While there are strong evidential and theoretical reasons for believing that memories are stored at synapses, the concept of a specialized “memory synapse” is rarely discussed. Here, we review the evidence that memories are stored at the synapse and consider the opposing possibilities. We argue that if memories are stored in an active fashion at synapses, then these memory synapses must have distinct molecular complexes that distinguish them from other synapses. In particular, examples from Aplysia sensory-motor neuron synapses and synapses on defined engram neurons in rodent models are discussed. Specific hypotheses for molecular complexes that define memory synapses are presented, including persistently active kinases, transmitter receptor complexes and trans-synaptic adhesion proteins. PMID:29695960

Rice Cellulose SynthaseA8 Plant-Conserved Region Is a Coiled-Coil at the Catalytic Core Entrance1[OPEN

PubMed Central

Rushton, Phillip S.; Olek, Anna T.; Makowski, Lee; Badger, John

2017-01-01

The crystallographic structure of a rice (Oryza sativa) cellulose synthase, OsCesA8, plant-conserved region (P-CR), one of two unique domains in the catalytic domain of plant CesAs, was solved to 2.4 Å resolution. Two antiparallel α-helices form a coiled-coil domain linked by a large extended connector loop containing a conserved trio of aromatic residues. The P-CR structure was fit into a molecular envelope for the P-CR domain derived from small-angle X-ray scattering data. The P-CR structure and molecular envelope, combined with a homology-based chain trace of the CesA8 catalytic core, were modeled into a previously determined CesA8 small-angle X-ray scattering molecular envelope to produce a detailed topological model of the CesA8 catalytic domain. The predicted position for the P-CR domain from the molecular docking models places the P-CR connector loop into a hydrophobic pocket of the catalytic core, with the coiled-coil aligned near the entrance of the substrate UDP-glucose into the active site. In this configuration, the P-CR coiled-coil alone is unlikely to regulate substrate access to the active site, but it could interact with other domains of CesA, accessory proteins, or other CesA catalytic domains to control substrate delivery. PMID:27879387

Modeling the protonation states of β-secretase binding pocket by molecular dynamics simulations and docking studies.

PubMed

Sabbah, Dima A; Zhong, Haizhen A

2016-07-01

β-secretase (BACE1) is an aspartyl protease that processes the β-amyloid peptide in the human brain in patients with Alzheimer's disease. There are two catalytic aspartates (ASP32 and ASP228) in the active domain of BACE1. Although it is believed that the net charge of the Asp dyad is -1, the exact protonation state still remains a matter of debate. We carried out molecular dynamic (MD) simulations for the four protonation states of BACE1 proteins. We applied Glide docking studies to 21 BACE1 inhibitors against the MD extracted conformations. The dynamic results infer that the protein/ligand complex remains stable during the entire simulation course for HD32D228 model. The results show that the hydrogen bonds between the inhibitor and the Asp dyad are maintained in the 10,000th ps snapshot of HD32D228 model. Our results also reveal the significant loop residues in maintaining the active binding conformation in the HD32D228 model. Molecular docking results show that the HD32D228 model provided the best enrichment factor score, suggesting that this model was able to recognize the most active compounds. Our observations provide an evidence for the preference of the anionic state (HD32D228) in BACE1 binding site and are in accord with reported computational data. The protonation state study would provide significant information to assign the correct protonation state for structure-based drug design and docking studies targeting the BACE1 proteins as a tactic to develop potential AD inhibitors. Copyright © 2016 Elsevier Inc. All rights reserved.

Application of Molecular Interaction Volume Model for Phase Equilibrium of Sn-Based Binary System in Vacuum Distillation

NASA Astrophysics Data System (ADS)

Kong, Lingxin; Yang, Bin; Xu, Baoqiang; Li, Yifu

2014-09-01

Based on the molecular interaction volume model (MIVM), the activities of components of Sn-Sb, Sb-Bi, Sn-Zn, Sn-Cu, and Sn-Ag alloys were predicted. The predicted values are in good agreement with the experimental data, which indicate that the MIVM is of better stability and reliability due to its good physical basis. A significant advantage of the MIVM lies in its ability to predict the thermodynamic properties of liquid alloys using only two parameters. The phase equilibria of Sn-Sb and Sn-Bi alloys were calculated based on the properties of pure components and the activity coefficients, which indicates that Sn-Sb and Sn-Bi alloys can be separated thoroughly by vacuum distillation. This study extends previous investigations and provides an effective and convenient model on which to base refining simulations for Sn-based alloys.

Inhibition of Gsk3b Reduces Nfkb1 Signaling and Rescues Synaptic Activity to Improve the Rett Syndrome Phenotype in Mecp2-Knockout Mice.

PubMed

Jorge-Torres, Olga C; Szczesna, Karolina; Roa, Laura; Casal, Carme; Gonzalez-Somermeyer, Louisa; Soler, Marta; Velasco, Cecilia D; Martínez-San Segundo, Pablo; Petazzi, Paolo; Sáez, Mauricio A; Delgado-Morales, Raúl; Fourcade, Stephane; Pujol, Aurora; Huertas, Dori; Llobet, Artur; Guil, Sonia; Esteller, Manel

2018-05-08

Rett syndrome (RTT) is the second leading cause of mental impairment in girls and is currently untreatable. RTT is caused, in more than 95% of cases, by loss-of-function mutations in the methyl CpG-binding protein 2 gene (MeCP2). We propose here a molecular target involved in RTT: the glycogen synthase kinase-3b (Gsk3b) pathway. Gsk3b activity is deregulated in Mecp2-knockout (KO) mice models, and SB216763, a specific inhibitor, is able to alleviate the clinical symptoms with consequences at the molecular and cellular levels. In vivo, inhibition of Gsk3b prolongs the lifespan of Mecp2-KO mice and reduces motor deficits. At the molecular level, SB216763 rescues dendritic networks and spine density, while inducing changes in the properties of excitatory synapses. Gsk3b inhibition can also decrease the nuclear activity of the Nfkb1 pathway and neuroinflammation. Altogether, our findings indicate that Mecp2 deficiency in the RTT mouse model is partially rescued following treatment with SB216763. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Mechanism of Urea Crystal Dissolution in Water from Molecular Dynamics Simulation.

PubMed

Anand, Abhinav; Patey, G N

2018-01-25

Molecular dynamics simulations are used to determine the mechanism of urea crystal dissolution in water under sink conditions. Crystals of cubic and tablet shapes are considered, and results are reported for four commonly used water models. The dissolution rates for different water models can differ considerably, but the overall dissolution mechanism remains the same. Urea dissolution occurs in three stages: a relatively fast initial stage, a slower intermediate stage, and a final stage. We show that the long intermediate stage is well described by classical rate laws, which assume that the dissolution rate is proportional to the active surface area. By carrying out simulations at different temperatures, we show that urea dissolution is an activated process, with an activation energy of ∼32 kJ mol -1 . Our simulations give no indication of a significant diffusion layer, and we conclude that the detachment of molecules from the crystal is the rate-determining step for dissolution. The results we report for urea are consistent with earlier observations for the dissolution of NaCl crystals. This suggests that the three-stage mechanism and classical rate laws might apply to the dissolution of other ionic and molecular crystals.

Targeting the cell wall of Mycobacterium tuberculosis: a molecular modeling investigation of the interaction of imipenem and meropenem with L,D-transpeptidase 2.

PubMed

Silva, José Rogério A; Bishai, William R; Govender, Thavendran; Lamichhane, Gyanu; Maguire, Glenn E M; Kruger, Hendrik G; Lameira, Jeronimo; Alves, Cláudio N

2016-01-01

The single crystal X-ray structure of the extracellular portion of the L,D-transpeptidase (ex-LdtMt2 - residues 120-408) enzyme was recently reported. It was observed that imipenem and meropenem inhibit activity of this enzyme, responsible for generating L,D-transpeptide linkages in the peptidoglycan layer of Mycobacterium tuberculosis. Imipenem is more active and isothermal titration calorimetry experiments revealed that meropenem is subjected to an entropy penalty upon binding to the enzyme. Herein, we report a molecular modeling approach to obtain a molecular view of the inhibitor/enzyme interactions. The average binding free energies for nine commercially available inhibitors were calculated using MM/GBSA and Solvation Interaction Energy (SIE) approaches and the calculated energies corresponded well with the available experimentally observed results. The method reproduces the same order of binding energies as experimentally observed for imipenem and meropenem. We have also demonstrated that SIE is a reasonably accurate and cost-effective free energy method, which can be used to predict carbapenem affinities for this enzyme. A theoretical explanation was offered for the experimental entropy penalty observed for meropenem, creating optimism that this computational model can serve as a potential computational model for other researchers in the field.

Increased PKA signaling disrupts recognition memory and spatial memory: role in Huntington's disease.

PubMed

Giralt, Albert; Saavedra, Ana; Carretón, Olga; Xifró, Xavier; Alberch, Jordi; Pérez-Navarro, Esther

2011-11-01

Huntington's disease (HD) patients and mouse models show learning and memory impairment even before the onset of motor symptoms. However, the molecular events involved in this cognitive decline are still poorly understood. Here, using three different paradigms, the novel object recognition test, the T-maze spontaneous alternation task and the Morris water maze, we detected severe cognitive deficits in the R6/1 mouse model of HD before the onset of motor symptoms. When we examined the putative molecular pathways involved in these alterations, we observed hippocampal cAMP-dependent protein kinase (PKA) hyper-activation in naïve R6/1 mice compared with wild-type (WT) mice, whereas extracellular signal-regulated kinase 1/2 and calcineurin activities were not modified. Increased PKA activity resulted in hyper-phosphorylation of its substrates N-methyl-D-aspartate receptor subunit 1, Ras-guanine nucleotide releasing factor-1 and striatal-enriched protein tyrosine phosphatase, but not cAMP-responsive element binding protein or the microtubule-associated protein tau. In correlation with the over-activation of the PKA pathway, we found a down-regulation of the protein levels of some phosphodiesterase (PDE) 4 family members. Similar molecular changes were found in the hippocampus of R6/2 mice and HD patients. Furthermore, chronic treatment of WT mice with the PDE4 inhibitor rolipram up-regulated PKA activity, and induced learning and memory deficits similar to those seen in R6 mice, but had no effect on R6/1 mice cognitive impairment. Importantly, hippocampal PKA inhibition by infusion of Rp-cAMPS restored long-term memory in R6/2 mice. Thus, our results suggest that occlusion of PKA-dependent processes is one of the molecular mechanisms underlying cognitive decline in R6 animals.

Chemical and molecular mechanisms of antioxidants: experimental approaches and model systems

PubMed Central

Lü, Jian-Ming; Lin, Peter H; Yao, Qizhi; Chen, Changyi

2010-01-01

Abstract Free radicals derived from oxygen, nitrogen and sulphur molecules in the biological system are highly active to react with other molecules due to their unpaired electrons. These radicals are important part of groups of molecules called reactive oxygen/nitrogen species (ROS/RNS), which are produced during cellular metabolism and functional activities and have important roles in cell signalling, apoptosis, gene expression and ion transportation. However, excessive ROS attack bases in nucleic acids, amino acid side chains in proteins and double bonds in unsaturated fatty acids, and cause oxidative stress, which can damage DNA, RNA, proteins and lipids resulting in an increased risk for cardiovascular disease, cancer, autism and other diseases. Intracellular antioxidant enzymes and intake of dietary antioxidants may help to maintain an adequate antioxidant status in the body. In the past decades, new molecular techniques, cell cultures and animal models have been established to study the effects and mechanisms of antioxidants on ROS. The chemical and molecular approaches have been used to study the mechanism and kinetics of antioxidants and to identify new potent antioxidants. Antioxidants can decrease the oxidative damage directly via reacting with free radicals or indirectly by inhibiting the activity or expression of free radical generating enzymes or enhancing the activity or expression of intracellular antioxidant enzymes. The new chemical and cell-free biological system has been applied in dissecting the molecular action of antioxidants. This review focuses on the research approaches that have been used to study oxidative stress and antioxidants in lipid peroxidation, DNA damage, protein modification as well as enzyme activity, with emphasis on the chemical and cell-free biological system. PMID:19754673

A Critical Assessment of Combined Ligand-based and Structure-based Approaches to hERG Channel Blocker Modeling

PubMed Central

Du-Cuny, Lei; Chen, Lu; Zhang, Shuxing

2014-01-01

Blockade of hERG channel prolongs the duration of the cardiac action potential and is a common reason for drug failure in preclinical safety trials. Therefore, it is of great importance to develop robust in silico tools to predict potential hERG blockers in the early stages of drug discovery and development. Herein we described comprehensive approaches to assess the discrimination of hERG-active and -inactive compounds by combining QSAR modeling, pharmacophore analysis, and molecular docking. Our consensus models demonstrated high predictive capacity and improved enrichment, and they could correctly classify 91.8% of 147 hERG blockers from 351 inactives. To further enhance our modeling effort, hERG homology models were constructed and molecular docking studies were conducted, resulting in high correlations (R2=0.81) between predicted and experimental binding affinities. We expect our unique models can be applied to efficient screening for hERG blockades, and our extensive understanding of the hERG-inhibitor interactions will facilitate the rational design of drugs devoid of hERG channel activity and hence with reduced cardiac toxicities. PMID:21902220

Molecular design of two sterol 14α-demethylase homology models and their interactions with the azole antifungals ketoconazole and bifonazole

NASA Astrophysics Data System (ADS)

Rupp, Bernd; Raub, Stephan; Marian, Christel; Höltje, Hans-Dieter

2005-03-01

Sterol 14α-demethylase (CYP51) is one of the known major targets for azole antifungals. Therapeutic side effects of these antifungals are based on interactions of the azoles with the human analogue enzyme. This study describes for the first time a comparison of a human CYP51 (HU-CYP51) homology model with a homology model of the fungal CYP51 of Candida albicans (CA-CYP51). Both models are constructed by using the crystal structure of Mycobacterium tuberculosis MT-CYP51 (PDB code: 1EA1). The binding mode of the azole ketoconazole is investigated in molecular dynamics simulations with the GROMACS force field. The usage of special parameters for the iron azole complex binding is necessary to obtain the correct complex geometry in the active site of the enzyme models. Based on the dynamics simulations it is possible to explain the enantioselectivity of the human enzyme and also to predict the binding mode of the isomers of ketoconazole in the active site of the fungal model.

Homology modeling, molecular docking and MD simulation studies to investigate role of cysteine protease from Xanthomonas campestris in degradation of Aβ peptide.

PubMed

Dhanavade, Maruti J; Jalkute, Chidambar B; Barage, Sagar H; Sonawane, Kailas D

2013-12-01

Cysteine protease is known to degrade amyloid beta peptide which is a causative agent of Alzheimer's disease. This cleavage mechanism has not been studied in detail at the atomic level. Hence, a three-dimensional structure of cysteine protease from Xanthomonas campestris was constructed by homology modeling using Geno3D, SWISS-MODEL, and MODELLER 9v7. All the predicted models were analyzed by PROCHECK and PROSA. Three-dimensional model of cysteine protease built by MODELLER 9v7 shows similarity with human cathepsin B crystal structure. This model was then used further for docking and simulation studies. The molecular docking study revealed that Cys17, His87, and Gln88 residues of cysteine protease form an active site pocket similar to human cathepsin B. Then the docked complex was refined by molecular dynamic simulation to confirm its stable behavior over the entire simulation period. The molecular docking and MD simulation studies showed that the sulfhydryl hydrogen atom of Cys17 of cysteine protease interacts with carboxylic oxygen of Lys16 of Aβ peptide indicating the cleavage site. Thus, the cysteine protease model from X. campestris having similarity with human cathepsin B crystal structure may be used as an alternate approach to cleave Aβ peptide a causative agent of Alzheimer's disease. © 2013 Elsevier Ltd. All rights reserved.

Molecular mechanisms of inner ear development.

PubMed

Wu, Doris K; Kelley, Matthew W

2012-08-01

The inner ear is a structurally complex vertebrate organ built to encode sound, motion, and orientation in space. Given its complexity, it is not surprising that inner ear dysfunction is a relatively common consequence of human genetic mutation. Studies in model organisms suggest that many genes currently known to be associated with human hearing impairment are active during embryogenesis. Hence, the study of inner ear development provides a rich context for understanding the functions of genes implicated in hearing loss. This chapter focuses on molecular mechanisms of inner ear development derived from studies of model organisms.

3D-QSAR Studies on a Series of Dihydroorotate Dehydrogenase Inhibitors: Analogues of the Active Metabolite of Leflunomide

PubMed Central

Li, Shun-Lai; He, Mao-Yu; Du, Hong-Guang

2011-01-01

The active metabolite of the novel immunosuppressive agent leflunomide has been shown to inhibit the enzyme dihydroorotate dehydrogenase (DHODH). This enzyme catalyzes the fourth step in de novo pyrimidine biosynthesis. Self-organizing molecular field analysis (SOMFA), a simple three-dimensional quantitative structure-activity relationship (3D-QSAR) method is used to study the correlation between the molecular properties and the biological activities of a series of analogues of the active metabolite. The statistical results, cross-validated rCV2 (0.664) and non cross-validated r2 (0.687), show a good predictive ability. The final SOMFA model provides a better understanding of DHODH inhibitor-enzyme interactions, and may be useful for further modification and improvement of inhibitors of this important enzyme. PMID:21686163

Real-time assessment of inflammation and treatment response in a mouse model of allergic airway inflammation

PubMed Central

Cortez-Retamozo, Virna; Swirski, Filip K.; Waterman, Peter; Yuan, Hushan; Figueiredo, Jose Luiz; Newton, Andita P.; Upadhyay, Rabi; Vinegoni, Claudio; Kohler, Rainer; Blois, Joseph; Smith, Adam; Nahrendorf, Matthias; Josephson, Lee; Weissleder, Ralph; Pittet, Mikael J.

2008-01-01

Eosinophils are multifunctional leukocytes that degrade and remodel tissue extracellular matrix through production of proteolytic enzymes, release of proinflammatory factors to initiate and propagate inflammatory responses, and direct activation of mucus secretion and smooth muscle cell constriction. Thus, eosinophils are central effector cells during allergic airway inflammation and an important clinical therapeutic target. Here we describe the use of an injectable MMP-targeted optical sensor that specifically and quantitatively resolves eosinophil activity in the lungs of mice with experimental allergic airway inflammation. Through the use of real-time molecular imaging methods, we report the visualization of eosinophil responses in vivo and at different scales. Eosinophil responses were seen at single-cell resolution in conducting airways using near-infrared fluorescence fiberoptic bronchoscopy, in lung parenchyma using intravital microscopy, and in the whole body using fluorescence-mediated molecular tomography. Using these real-time imaging methods, we confirmed the immunosuppressive effects of the glucocorticoid drug dexamethasone in the mouse model of allergic airway inflammation and identified a viridin-derived prodrug that potently inhibited the accumulation and enzyme activity of eosinophils in the lungs. The combination of sensitive enzyme-targeted sensors with noninvasive molecular imaging approaches permitted evaluation of airway inflammation severity and was used as a model to rapidly screen for new drug effects. Both fluorescence-mediated tomography and fiberoptic bronchoscopy techniques have the potential to be translated into the clinic. PMID:19033674

Charge Transport Processes in Molecular Junctions

NASA Astrophysics Data System (ADS)

Smith, Christopher Eugene

Molecular electronics (ME) has evolved into a rich area of exploration that combines the fields of chemistry, materials, electronic engineering and computational modeling to explore the physics behind electronic conduction at the molecular level. Through studying charge transport properties of single molecules and nanoscale molecular materials the field has gained the potential to bring about new avenues for the miniaturization of electrical components where quantum phenomena are utilized to achieve solid state molecular device functionality. Molecular junctions are platforms that enable these studies and consist of a single molecule or a small group of molecules directly connected to electrodes. The work presented in this thesis has built upon the current understanding of the mechanisms of charge transport in ordered junctions using self-assembled monolayer (SAM) molecular thin films. Donor and acceptor compounds were synthesized and incorporated into SAMs grown on metal substrates then the transport properties were measured with conducting probe atomic force microscopy (CP-AFM). In addition to experimentally measured current-voltage (I-V) curves, the transport properties were addressed computationally and modeled theoretically. The key objectives of this project were to 1) investigate the impact of molecular structure on hole and electron charge transport, 2) understand the nature of the charge carriers and their structure-transport properties through long (<4 nm) conjugated molecular wires, and 3) quantitatively extract interfacial properties characteristic to macroscopic junctions, such as energy level alignment and molecule-contact electronic coupling from experimental I-V curves. Here, we lay ground work for creating a more complete picture of charge transport in macroscopically ordered molecular junctions of controlled architecture, length and charge carrier. The polaronic nature of hopping transport has been predicted in long, conjugated molecular wires. Using quantum-based calculations, we modeled 'p-type' polaron transport through oligophenylenethiophene (OPTI) wires and assigned transport activation energies to specific modes of nuclear motion. We also show control over 'n-type', LUMO-mediated transport in short ( 2 nm) redox-active perylenediimide (PDI) SAMs bound to contacts through isocyano linkers. By changing the contact work function (φ) and temperature, we were able to verify thermally-assisted LUMO transport. Transition voltage spectroscopy and the single level model was employed to fit the experimental I-V curves and extract the electronic coupling (epsilon) and the EF-LUMO offset (epsilonl). It was found that epsilonl does not change with φ (LUMO pinning), while Gamma changes with both φ and temperature. Further, the PDI SAMs could be reversibly chemically gated to modulate the transport. These results help advance our understanding of transport behavior in semiconducting molecular thin films, and open opportunities to engineer improved electronic functionality into molecular devices.

Acquired MET expression confers resistance to EGFR inhibition in a mouse model of glioblastoma multiforme.

PubMed

Jun, H J; Acquaviva, J; Chi, D; Lessard, J; Zhu, H; Woolfenden, S; Bronson, R T; Pfannl, R; White, F; Housman, D E; Iyer, L; Whittaker, C A; Boskovitz, A; Raval, A; Charest, A

2012-06-21

Glioblastoma multiforme (GBM) is an aggressive brain tumor for which there is no cure. Overexpression of wild-type epidermal growth factor receptor (EGFR) and loss of the tumor suppressor genes Ink4a/Arf and PTEN are salient features of this deadly cancer. Surprisingly, targeted inhibition of EGFR has been clinically disappointing, demonstrating an innate ability for GBM to develop resistance. Efforts at modeling GBM in mice using wild-type EGFR have proven unsuccessful to date, hampering endeavors at understanding molecular mechanisms of therapeutic resistance. Here, we describe a unique genetically engineered mouse model of EGFR-driven gliomagenesis that uses a somatic conditional overexpression and chronic activation of wild-type EGFR in cooperation with deletions in the Ink4a/Arf and PTEN genes in adult brains. Using this model, we establish that chronic activation of wild-type EGFR with a ligand is necessary for generating tumors with histopathological and molecular characteristics of GBMs. We show that these GBMs are resistant to EGFR kinase inhibition and we define this resistance molecularly. Inhibition of EGFR kinase activity using tyrosine kinase inhibitors in GBM tumor cells generates a cytostatic response characterized by a cell cycle arrest, which is accompanied by a substantial change in global gene expression levels. We demonstrate that an important component of this pattern is the transcriptional activation of the MET receptor tyrosine kinase and that pharmacological inhibition of MET overcomes the resistance to EGFR inhibition in these cells. These findings provide important new insights into mechanisms of resistance to EGFR inhibition and suggest that inhibition of multiple targets will be necessary to provide therapeutic benefit for GBM patients.

Xenobiotic Nuclear Receptor Signaling Determines Molecular Pathogenesis of Progressive Familial Intrahepatic Cholestasis.

PubMed

Kim, Kang Ho; Choi, Jong Min; Li, Feng; Arizpe, Armando; Wooton-Kee, Clavia Ruth; Anakk, Sayeepriyadarshini; Jung, Sung Yun; Finegold, Milton J; Moore, David D

2018-06-01

Progressive familial intrahepatic cholestasis (PFIC) is a genetically heterogeneous disorder of bile flow disruption due to abnormal canalicular transport or impaired bile acid (BA) metabolism, causing excess BA accumulation and liver failure. We previously reported an intrahepatic cholestasis mouse model based on loss of function of both farnesoid X receptor (FXR; NR1H4) and a small heterodimer partner (SHP; NR0B2) [double knockout (DKO)], which has strong similarities to human PFIC5. We compared the pathogenesis of DKO livers with that of another intrahepatic cholestasis model, Bsep-/-, which represents human PFIC2. Both models exhibit severe hepatomegaly and hepatic BA accumulation, but DKO showed greater circulating BA and liver injury, and Bsep-/- had milder phenotypes. Molecular profiling of BAs uncovered specific enrichment of cholic acid (CA)-derived BAs in DKO livers but chenodeoxycholate-derived BAs in Bsep-/- livers. Transcriptomic and proteomic analysis revealed specific activation of CA synthesis and alternative basolateral BA transport in DKO but increased chenodeoxycholic acid synthesis and canalicular transport in Bsep-/-. The constitutive androstane receptor (CAR)/pregnane X receptor (PXR)-CYP2B/CYP2C axis is activated in DKO livers but not in other cholestasis models. Loss of this axis in Fxr:Shp:Car:Pxr quadruple knockouts blocked Cyp2b/Cyp2c gene induction, impaired bilirubin conjugation/elimination, and increased liver injury. Differential CYP2B expression in DKO and Bsep-/- was recapitulated in human PFIC5 and PFIC2 livers. In conclusion, loss of FXR/SHP results in distinct molecular pathogenesis and CAR/PXR activation, which promotes Cyp2b/Cyp2c gene transcription and bilirubin clearance. CAR/PXR activation was not observed in Bsep-/- mice or PFIC2 patients. These findings provide a deeper understanding of the heterogeneity of intrahepatic cholestasis.

An integrated molecular modeling approach for in silico design of new tetracyclic derivatives as ALK inhibitors.

PubMed

Peddi, Saikiran Reddy; Sivan, Sree Kanth; Manga, Vijjulatha

2016-10-01

Anaplastic lymphoma kinase (ALK), a promising therapeutic target for treatment of human cancers, is a receptor tyrosine kinase that instigates the activation of several signal transduction pathways. In the present study, in silico methods have been employed in order to explore the structural features and functionalities of a series of tetracyclic derivatives displaying potent inhibitory activity toward ALK. Initially docking was performed using GLIDE 5.6 to probe the bioactive conformation of all the compounds and to understand the binding modes of inhibitors. The docking results revealed that ligand interaction with Met 1199 plays a crucial role in binding of inhibitors to ALK. Further to establish a robust 3D-QSAR model using CoMFA and CoMSIA methods, the whole dataset was divided into three splits. Model obtained from Split 3 showed high accuracy ([Formula: see text] of 0.700 and 0.682, [Formula: see text] of 0.971 and 0.974, [Formula: see text] of 0.673 and 0.811, respectively for CoMFA and CoMSIA). The key structural requirements for enhancing the inhibitory activity were derived from CoMFA and CoMSIA contours in combination with site map analysis. Substituting small electronegative groups at Position 8 by replacing either morpholine or piperidine rings and maintaining hydrophobic character at Position 9 in tetracyclic derivatives can enhance the inhibitory potential. Finally, we performed molecular dynamics simulations in order to investigate the stability of protein ligand interactions and MM/GBSA calculations to compare binding free energies of co-crystal ligand and newly designed molecule N1. Based on the coherence of outcome of various molecular modeling studies, a set of 11 new molecules having potential predicted inhibitory activity were designed.

RAMBAs for Breast Cancer Prevention and Treatment

DTIC Science & Technology

2009-01-01

activated by CYPs only in cancer cells. Finally, the expression of CYPs within tumors has been utilized in the development of bioreductive molecules...enable us to utilize the Catalyst molecular modeling program to create a general phar- macophore model that can differentiate compounds as active or...the discovery and char- acterization of retinoid receptor and the realization of these compounds as nonsteroidal small-molecule hor- mones .1 All-trans

Molecular docking, 3D QSAR and dynamics simulation studies of imidazo-pyrrolopyridines as janus kinase 1 (JAK 1) inhibitors.

PubMed

Itteboina, Ramesh; Ballu, Srilata; Sivan, Sree Kanth; Manga, Vijjulatha

2016-10-01

Janus kinase 1 (JAK 1) plays a critical role in initiating responses to cytokines by the JAK-signal transducer and activator of transcription (JAK-STAT). This controls survival, proliferation and differentiation of a variety of cells. Docking, 3D quantitative structure activity relationship (3D-QSAR) and molecular dynamics (MD) studies were performed on a series of Imidazo-pyrrolopyridine derivatives reported as JAK 1 inhibitors. QSAR model was generated using 30 molecules in the training set; developed model showed good statistical reliability, which is evident from r 2 ncv and r 2 loo values. The predictive ability of this model was determined using a test set of 13 molecules that gave acceptable predictive correlation (r 2 Pred ) values. Finally, molecular dynamics simulation was performed to validate docking results and MM/GBSA calculations. This facilitated us to compare binding free energies of cocrystal ligand and newly designed molecule R1. The good concordance between the docking results and CoMFA/CoMSIA contour maps afforded obliging clues for the rational modification of molecules to design more potent JAK 1 inhibitors. Copyright © 2016 Elsevier Ltd. All rights reserved.

Molecular modeling and analysis of human and plant endo-β-N-acetyl- glucosaminidases for mutations effects on function

PubMed Central

Choragudi, Shechinah Felice; Veeramachaneni, Ganesh Kumar; Raman, BV; JS, Bondili

2014-01-01

Endo- β-N-acetylgucosaminidases (ENGases) are the enzymes that catalyze both hydrolysis and transglycosylation reactions. It is of interest to study ENGases because of their ability to synthesize glycopeptides. Homology models of Human, Arabidopsis thaliana and Sorghum ENGases were developed and their active sites marked based on information available from Arthrobacter protophormiae (PDB ID: 3FHQ) ENGase. Further, these models were docked with the natural substrate GlcNAc-Asn and the inhibitor Man3GlcNAc-thiazoline. The catalytic triad of Asn, Glu and Tyr (N171, E173 and Y205 of bacteria) were found to be conserved across the phyla. The crucial Y299F mutation showing 3 times higher transglycosylation activity than in wild type Endo-A is known. The hydrolytic activity remained unchanged in bacteria, while the transglycosylation activity increased. This Y to F change is found to be naturally evolved and should be attributing higher transglycosylation rates in human and Arabidopsis thaliana ENGases. Ligand interactions Ligplots revealed the interaction of amino acids with hydrophobic side chains and polar uncharged side chain amino acids. Thus, structure based molecular model-ligand interactions provide insights into the catalytic mechanism of ENGases and assist in the rational engineering of ENGases. PMID:25258486

Molecular modeling and analysis of human and plant endo-β-N-acetyl- glucosaminidases for mutations effects on function.

PubMed

Choragudi, Shechinah Felice; Veeramachaneni, Ganesh Kumar; Raman, Bv; Js, Bondili

2014-01-01

Endo- β-N-acetylgucosaminidases (ENGases) are the enzymes that catalyze both hydrolysis and transglycosylation reactions. It is of interest to study ENGases because of their ability to synthesize glycopeptides. Homology models of Human, Arabidopsis thaliana and Sorghum ENGases were developed and their active sites marked based on information available from Arthrobacter protophormiae (PDB ID: 3FHQ) ENGase. Further, these models were docked with the natural substrate GlcNAc-Asn and the inhibitor Man3GlcNAc-thiazoline. The catalytic triad of Asn, Glu and Tyr (N171, E173 and Y205 of bacteria) were found to be conserved across the phyla. The crucial Y299F mutation showing 3 times higher transglycosylation activity than in wild type Endo-A is known. The hydrolytic activity remained unchanged in bacteria, while the transglycosylation activity increased. This Y to F change is found to be naturally evolved and should be attributing higher transglycosylation rates in human and Arabidopsis thaliana ENGases. Ligand interactions Ligplots revealed the interaction of amino acids with hydrophobic side chains and polar uncharged side chain amino acids. Thus, structure based molecular model-ligand interactions provide insights into the catalytic mechanism of ENGases and assist in the rational engineering of ENGases.

Molecular imaging assessment of periodontitis lesions in an experimental mouse model.

PubMed

Ideguchi, Hidetaka; Yamashiro, Keisuke; Yamamoto, Tadashi; Shimoe, Masayuki; Hongo, Shoichi; Kochi, Shinsuke; Yoshihara-Hirata, Chiaki; Aoyagi, Hiroaki; Kawamura, Mari; Takashiba, Shogo

2018-06-06

We aimed to evaluate molecular imaging as a novel diagnostic tool for mice periodontitis model induced by ligature and Porphyromonas gingivalis (Pg) inoculation. Twelve female mice were assigned to the following groups: no treatment as control group (n = 4); periodontitis group induced by ligature and Pg as Pg group (n = 4); and Pg group treated with glycyrrhizinic acid (GA) as Pg + GA group (n = 4). All mice were administered a myeloperoxidase (MPO) activity-specific luminescent probe and observed using a charge-coupled device camera on day 14. Image analysis on all mice was conducted using software to determine the signal intensity of inflammation. Additionally, histological and radiographic evaluation for periodontal inflammation and bone resorption at the site of periodontitis, and quantitative enzyme-linked immunosorbent assay (ELISA) were conducted on three mice for each group. Each experiment was performed three times. Levels of serum IgG antibody against P. gingivalis were significantly higher in the Pg than in the Pg + GA group. Histological analyses indicated that the number of osteoclasts and neutrophils were significantly lower in the Pg + GA than in the Pg group. Micro-CT image analysis indicated no difference in bone resorption between the Pg and Pg + GA groups. The signal intensity of MPO activity was detected on the complete craniofacial image; moreover, strong signal intensity was localized specifically at the periodontitis site in the ex vivo palate, with group-wise differences. Molecular imaging analysis based on MPO activity showed high sensitivity of detection of periodontal inflammation in mice. Molecular imaging analysis based on MPO activity has potential as a diagnostic tool for periodontitis.

Corin mutations K317E and S472G from preeclamptic patients alter zymogen activation and cell surface targeting. [Corrected].

PubMed

Dong, Ningzheng; Zhou, Tiantian; Zhang, Yue; Liu, Meng; Li, Hui; Huang, Xiaoyi; Liu, Zhenzhen; Wu, Yi; Fukuda, Koichi; Qin, Jun; Wu, Qingyu

2014-06-20

Corin is a membrane-bound serine protease that acts as the atrial natriuretic peptide (ANP) convertase in the heart. Recent studies show that corin also activates ANP in the pregnant uterus to promote spiral artery remodeling and prevent pregnancy-induced hypertension. Two CORIN gene mutations, K317E and S472G, were identified in preeclamptic patients and shown to have reduced activity in vitro. In this study, we carried out molecular modeling and biochemical experiments to understand how these mutations impair corin function. By molecular modeling, the mutation K317E was predicted to alter corin LDL receptor-2 module conformation. Western blot analysis of K317E mutant in HEK293 cells showed that the mutation did not block corin expression on the cell surface but inhibited corin zymogen activation. In contrast, the mutation S472G was predicted to abolish a β-sheet critical for corin frizzled-2 module structure. In Western blot analysis and flow cytometry, S472G mutant was not detected on the cell surface in transfected HEK293 cells. By immunostaining, the S472G mutant was found in the ER, indicating that the mutation S472G disrupted the β-sheet, causing corin misfolding and ER retention. Thus, these results show that mutations in the CORIN gene may impair corin function by entirely different mechanisms. Together, our data provide important insights into the molecular basis underlying corin mutations that may contribute to preeclampsia in patients. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Numerical studies from quantum to macroscopic scales of carbon nanoparticules in hydrogen plasma

NASA Astrophysics Data System (ADS)

Lombardi, Guillaume; Ngandjong, Alain; Mezei, Zsolt; Mougenot, Jonathan; Michau, Armelle; Hassouni, Khaled; Seydou, Mahamadou; Maurel, François

2016-09-01

Dusty plasmas take part in large scientific domains from Universe Science to nanomaterial synthesis processes. They are often generated by growth from molecular precursor. This growth leads to the formation of larger clusters which induce solid germs nucleation. Particle formed are described by an aerosol dynamic taking into account coagulation, molecular deposition and transport processes. These processes are controlled by the elementary particle. So there is a strong coupling between particle dynamics and plasma discharge equilibrium. This study is focused on the development of a multiscale physic and numeric model of hydrogen plasmas and carbon particles around three essential coupled axes to describe the various physical phenomena: (i) Macro/mesoscopic fluid modeling describing in an auto-coherent way, characteristics of the plasma, molecular clusters and aerosol behavior; (ii) the classic molecular dynamics offering a description to the scale molecular of the chains of chemical reactions and the phenomena of aggregation; (iii) the quantum chemistry to establish the activation barriers of the different processes driving the nanopoarticule formation.

Anti-cholelithogenic potential of dietary spices and their bioactives.

PubMed

Srinivasan, Krishnapura

2017-05-24

Dietary hypocholesterolemic spices-curcumin (active compound of turmeric (Curcuma longa)) and capsaicin (active compound of red pepper (Capsicum annuum)), the active principles of spices-turmeric (Curcuma longa) and red pepper (Capsicum annuum), fenugreek (Trigonella foenum-graecum) seeds, garlic (Allium sativum), and onion (Allium cepa) are documented to have anti-cholelithogenic property in animal model. These spices prevent the induction of cholesterol gallstones by lithogenic high cholesterol diet and also regress the pre-established cholesterol gallstones, by virtue of their hypolipidemic potential. The antilithogenic influence of these spices is primarily attributable to their hypocholesterolemic effect. Increased cholesterol saturation index, cholesterol:phospholipid ratio and cholesterol:bile acid ratio in the bile caused by the lithogenic diet was countered by these spices. The antilithogenicity of these hypocholesterolemic spices was considered to be due also to their influence on biliary proteins that have pro-nucleating activity and anti-nucleating activity. Investigations on the involvement of biliary proteins in cholesterol crystal nucleation revealed that in an in vitro bile model, low molecular weight biliary proteins of the lithogenic diet fed animals have a pro-nucleating activity. On the contrary, low molecular weight biliary proteins of the animals fed hypocholesterolemic spices along with lithogenic diet showed a potent anti-nucleating activity.

Synthesis, antimicrobial, anti-biofilm evaluation, and molecular modelling study of new chalcone linked amines derivatives.

PubMed

El-Messery, Shahenda M; Habib, El-Sayed E; Al-Rashood, Sarah T A; Hassan, Ghada S

2018-12-01

A series of amide chalcones conjugated with different secondary amines were synthesised and characterised by different spectroscopic techniques 1 H NMR, 13 C NMR, and ESI-MS. They were screened for in vitro antibacterial activity. Compounds 36, 37, 38, 42, and 44 are the most active among the synthesised series exhibiting MIC value of 2.0-10.0 µg/ml against different bacterial strains. Compound 36 was equipotent to the standard drug Ampicillin displaying MBC value of 2.0 µg/ml against the bacterial strain Staphylococcus aureus. The products were screened for anti-biofilm activity. Compounds 36, 37, and 38 exhibited promising anti-biofilm activity with IC 50 value ranges from 2.4 to 8.6 µg. Molecular modelling was performed suggesting parameters of signalling anti-biofilm mechanism. AspB327 HisB340 (arene-arene interaction) and IleB328 amino acid residues seemed of higher importance to inhibit c-di-GMP. Hydrophobicity may be crucial for activity. ADME calculations suggested that compounds 36, 37, and 38 could be used as good orally absorbed anti-biofilm agents.

Molecular interactions between fenoterol stereoisomers and derivatives and the β₂-adrenergic receptor binding site studied by docking and molecular dynamics simulations.

PubMed

Plazinska, Anita; Kolinski, Michal; Wainer, Irving W; Jozwiak, Krzysztof

2013-11-01

The β2 adrenergic receptor (β2-AR) has become a model system for studying the ligand recognition process and mechanism of the G protein coupled receptors activation. In the present study stereoisomers of fenoterol and some of its derivatives (N = 94 molecules) were used as molecular probes to identify differences in stereo-recognition interactions between β2-AR and structurally similar agonists. The present study aimed at determining the 3D molecular models of the fenoterol derivative-β2-AR complexes. Molecular models of β2-AR have been developed by using the crystal structure of the human β2-AR T4 lysozyme fusion protein with bound (S)-carazolol (PDB ID: 2RH1) and more recently reported structure of a nanobody-stabilized active state of the β2-AR with the bound full agonist BI-167107 (PDB ID: 3P0G). The docking procedure allowed us to study the similarities and differences in the recognition binding site(s) for tested ligands. The agonist molecules occupied the same binding region, between TM III, TM V, TM VI and TM VII. The residues identified by us during docking procedure (Ser203, Ser207, Asp113, Lys305, Asn312, Tyr308, Asp192) were experimentally indicated in functional and biophysical studies as being very important for the agonist-receptor interactions. Moreover, the additional space, an extension of the orthosteric pocket, was identified and described. Furthermore, the molecular dynamics simulations were used to study the molecular mechanism of interaction between ligands ((R,R')- and (S,S')-fenoterol) and β2-AR. Our research offers new insights into the ligand stereoselective interaction with one of the most important GPCR member. This study may also facilitate the design of improved selective medications, which can be used to treat, prevent and control heart failure symptoms.

Simulation of carbohydrates, from molecular docking to dynamics in water.

PubMed

Sapay, Nicolas; Nurisso, Alessandra; Imberty, Anne

2013-01-01

Modeling of carbohydrates is particularly challenging because of the variety of structures resulting for the high number of monosaccharides and possible linkages and also because of their intrinsic flexibility. The development of carbohydrate parameters for molecular modeling is still an active field. Nowadays, main carbohydrates force fields are GLYCAM06, CHARMM36, and GROMOS 45A4. GLYCAM06 includes the largest choice of compounds and is compatible with the AMBER force fields and associated. Furthermore, AMBER includes tools for the implementation of new parameters. When looking at protein-carbohydrate interaction, the choice of the starting structure is of importance. Such complex can be sometimes obtained from the Protein Data Bank-although the stereochemistry of sugars may require some corrections. When no experimental data is available, molecular docking simulation is generally used to the obtain protein-carbohydrate complex coordinates. As molecular docking parameters are not specifically dedicated to carbohydrates, inaccuracies should be expected, especially for the docking of polysaccharides. This issue can be addressed at least partially by combining molecular docking with molecular dynamics simulation in water.

Design, synthesis, antiviral bioactivity and three-dimensional quantitative structure-activity relationship study of novel ferulic acid ester derivatives containing quinazoline moiety.

PubMed

Wu, Zengxue; Zhang, Jian; Chen, Jixiang; Pan, Jianke; Zhao, Lei; Liu, Dengyue; Zhang, Awei; Chen, Jin; Hu, Deyu; Song, Baoan

2017-10-01

Ferulic acid and quinazoline derivatives possess good antiviral activities. In order to develop novel compounds with high antiviral activities, a series of ferulic acid ester derivatives containing quinazoline were synthesized and evaluated for their antiviral activities. Bioassays indicated that some of the compounds exhibited good antiviral activities in vivo against tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV). One of the compounds demonstrated significant curative and protective activities against TMV and CMV, with EC 50 values of 162.14, 114.61 and 255.49, 138.81 mg L -1 , respectively, better than those of ningnanmycin (324.51, 168.84 and 373.88, 272.70 mg L -1 ). The values of q 2 and r 2 for comparative molecular field analysis and comparative molecular similarity index analysis in the TMV (0.508, 0.663 and 0.992, 0.930) and CMV (0.530, 0.626 and 0.997, 0.981) models presented good predictive abilities. Some of the title compounds demonstrated good antiviral activities. Three-dimensional quantitative structure-activity relationship models revealed that the antiviral activities depend on steric and electrostatic properties. These results could provide significant structural insights for the design of highly active ferulic acid derivatives. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

Combating oxidative stress as a hallmark of cancer and aging: Computational modeling and synthesis of phenylene diamine analogs as potential antioxidant.

PubMed

Abou-Zeid, Laila; Baraka, Hany N

2014-07-01

The cross talk between the over expression of oxygen-free radicals is known as reactive oxygen species (ROS) that is associated with the excessive telomerase activity (TA). Telomerase activity is an invariable finding where human telomerase (hTERT) has been implicated in tumor oxidative stress and redox-mediated malignancy. The hTERT over expression is a novel tumor marker and is promising as a novel class of therapeutic weapons to fight against cancer. A new series of phenylene diamines were designed, synthesized, and evaluated for their in vitro antioxidant as an indicator of inhibiting the oxidative stress tumor. Compounds 3b and 7b proved to be the most active antioxidants with high percentage ABTS inhibition ranged from 89.40% to 88.59% respectively. Molecular modeling studies indicated that the crest configuration of phenylene diamine nucleus with substitutions of trimethoxy benzamido functional proved to be crucial for enhancing the free radical scavenging activity. Molecular modeling exploration indicated the proper binding selectivity of the 3b and 7b to the 3KYL pocket with promising hTERT inhibitors as a hallmark of cancer.

Scientific Communication and the Unified Laboratory Sequence1

NASA Astrophysics Data System (ADS)

Silverstein, Todd P.; Hudak, Norman J.; Chapple, Frances H.; Goodney, David E.; Brink, Christina P.; Whitehead, Joyce P.

1997-02-01

The "Temperature Dependent Relaxation Kinetics" lab was first implemented in 1987; it uses stopped-flow pH jump techniques to determine rate constants and activation parameters (H, S, G) for a reaction mechanism. Two new experiments (Monoamine Oxidase, and Molecular Modeling) will be implemented in the fall of 1997. The "Monoamine Oxidase" project uses chromatography and spectrophotometry to purify and characterize the enzyme. Subsequent photometric assays explore the enzyme's substrate specificity, activation energy, and denaturation. Finally, in the "Molecular Modeling"project, students characterize enzyme - substrate and drug - receptor interactions. Energy minimization protocols are used to make predictions about protein structure and ligand binding, and to explore pharmacological and biomedical implications. With these additions, the twelve Unified Laboratory projects introduce our chemistry majors to nearly all of the instrumental methods commonly encountered in modern chemistry.

Molecular modeling of ligand-receptor interactions in the OR5 olfactory receptor.

PubMed

Singer, M S; Shepherd, G M

1994-06-02

Olfactory receptors belong to the superfamily of seven transmembrane domain, G protein-coupled receptors. In order to begin analysis of mechanisms of receptor activation, a computer model of the OR5 olfactory receptor has been constructed and compared with other members of this superfamily. We have tested docking of the odor molecule lyral, which is known to activate the OR5 receptor. The results point to specific ligand-binding residues on helices III through VII that form a binding pocket in the receptor. Some of these residues occupy sequence positions identical to ligand-binding residues conserved among other superfamily members. The results provide new insights into possible molecular mechanisms of odor recognition and suggest hypotheses to guide future experimental studies using site-directed mutagenesis.

First-Principles Quantum Dynamics of Singlet Fission: Coherent versus Thermally Activated Mechanisms Governed by Molecular π Stacking

NASA Astrophysics Data System (ADS)

Tamura, Hiroyuki; Huix-Rotllant, Miquel; Burghardt, Irene; Olivier, Yoann; Beljonne, David

2015-09-01

Singlet excitons in π -stacked molecular crystals can split into two triplet excitons in a process called singlet fission that opens a route to carrier multiplication in photovoltaics. To resolve controversies about the mechanism of singlet fission, we have developed a first principles nonadiabatic quantum dynamical model that reveals the critical role of molecular stacking symmetry and provides a unified picture of coherent versus thermally activated singlet fission mechanisms in different acenes. The slip-stacked equilibrium packing structure of pentacene derivatives is found to enhance ultrafast singlet fission mediated by a coherent superexchange mechanism via higher-lying charge transfer states. By contrast, the electronic couplings for singlet fission strictly vanish at the C2 h symmetric equilibrium π stacking of rubrene. In this case, singlet fission is driven by excitations of symmetry-breaking intermolecular vibrations, rationalizing the experimentally observed temperature dependence. Design rules for optimal singlet fission materials therefore need to account for the interplay of molecular π -stacking symmetry and phonon-induced coherent or thermally activated mechanisms.

Creating and Using Interactive, 3D-Printed Models to Improve Student Comprehension of the Bohr Model of the Atom, Bond Polarity, and Hybridization

ERIC Educational Resources Information Center

Smiar, Karen; Mendez, J. D.

2016-01-01

Molecular model kits have been used in chemistry classrooms for decades but have seen very little recent innovation. Using 3D printing, three sets of physical models were created for a first semester, introductory chemistry course. Students manipulated these interactive models during class activities as a supplement to existing teaching tools for…

Molecular Docking and Site-directed Mutagenesis of a Bacillus thuringiensis Chitinase to Improve Chitinolytic, Synergistic Lepidopteran-larvicidal and Nematicidal Activities

PubMed Central

Ni, Hong; Zeng, Siquan; Qin, Xu; Sun, Xiaowen; Zhang, Shan; Zhao, Xiuyun; Yu, Ziniu; Li, Lin

2015-01-01

Bacterial chitinases are useful in the biocontrol of agriculturally important pests and fungal pathogens. However, the utility of naturally occurring bacterial chitinases is often limited by their low enzyme activity. In this study, we constructed mutants of a Bacillus thuringiensis chitinase with enhanced activity based on homology modeling, molecular docking, and the site-directed mutagenesis of target residues to modify spatial positions, steric hindrances, or hydrophilicity/hydrophobicity. We first identified a gene from B. thuringiensis YBT-9602 that encodes a chitinase (Chi9602) belonging to glycosyl hydrolase family 18 with conserved substrate-binding and substrate-catalytic motifs. We constructed a structural model of a truncated version of Chi9602 (Chi960235-459) containing the substrate-binding domain using the homologous 1ITX protein of Bacillus circulans as the template. We performed molecular docking analysis of Chi960235-459 using di-N-acetyl-D-glucosamine as the ligand. We then selected 10 residues of interest from the docking area for the site-directed mutagenesis experiments and expression in Escherichia coli. Assays of the chitinolytic activity of the purified chitinases revealed that the three mutants exhibited increased chitinolytic activity. The ChiW50A mutant exhibited a greater than 60 % increase in chitinolytic activity, with similar pH, temperature and metal ion requirements, compared to wild-type Chi9602. Furthermore, ChiW50A exhibited pest-controlling activity and antifungal activity. Remarkable synergistic effects of this mutant with B. thuringiensis spore-crystal preparations against Helicoverpa armigera and Caenorhabditis elegans larvae and obvious activity against several plant-pathogenic fungi were observed. PMID:25678849

Application of the compensated Arrhenius formalism to fluidity data of polar organic liquids.

PubMed

Petrowsky, Matt; Fleshman, Allison M; Frech, Roger

2013-03-14

The temperature dependence of viscosity (the reciprocal of fluidity) in polar liquids has been studied for over a century, but the available theoretical models have serious limitations. Consequently, the viscosity is often described with empirical equations using adjustable fitting parameters that offer no insight into the molecular mechanism of transport. We have previously reported a novel approach called the compensated Arrhenius formalism (CAF) to describe ionic conductivity, self-diffusion, and dielectric relaxation in terms of molecular and system properties. Here the CAF is applied to fluidity data of pure n-acetates, 2-ketones, n-nitriles, and n-alcohols over the temperature range 5-85 °C. The fluidity is represented as an Arrhenius-like expression that includes a static dielectric constant dependence in the exponential prefactor. The dielectric constant dependence results from the dependence of mass and charge transport on the molecular dipole moment and the solvent dipole density. The CAF is the only self-consistent description of fluid transport in polar liquids written solely in terms of molecular and system parameters. A scaling procedure is used to calculate the activation energy for transport. We find that the activation energies for fluidity of the aprotic liquids are comparable in value, whereas a higher average E(a) value is observed for the n-alcohol data. Finally, we contrast the molecular description of transport presented here with the conventional hydrodynamic model.

Cardiac myosin missense mutations cause dilated cardiomyopathy in mouse models and depress molecular motor function.

PubMed

Schmitt, Joachim P; Debold, Edward P; Ahmad, Ferhaan; Armstrong, Amy; Frederico, Andrea; Conner, David A; Mende, Ulrike; Lohse, Martin J; Warshaw, David; Seidman, Christine E; Seidman, J G

2006-09-26

Dilated cardiomyopathy (DCM) leads to heart failure, a leading cause of death in industrialized nations. Approximately 30% of DCM cases are genetic in origin, with some resulting from point mutations in cardiac myosin, the molecular motor of the heart. The effects of these mutations on myosin's molecular mechanics have not been determined. We have engineered two murine models characterizing the physiological, cellular, and molecular effects of DCM-causing missense mutations (S532P and F764L) in the alpha-cardiac myosin heavy chain and compared them with WT mice. Mutant mice developed morphological and functional characteristics of DCM consistent with the human phenotypes. Contractile function of isolated myocytes was depressed and preceded left ventricular dilation and reduced fractional shortening. In an in vitro motility assay, both mutant cardiac myosins exhibited a reduced ability to translocate actin (V(actin)) but had similar force-generating capacities. Actin-activated ATPase activities were also reduced. Single-molecule laser trap experiments revealed that the lower V(actin) in the S532P mutant was due to a reduced ability of the motor to generate a step displacement and an alteration of the kinetics of its chemomechanical cycle. These results suggest that the depressed molecular function in cardiac myosin may initiate the events that cause the heart to remodel and become pathologically dilated.

Discovery of novel inhibitors of Mycobacterium tuberculosis MurG: homology modelling, structure based pharmacophore, molecular docking, and molecular dynamics simulations.

PubMed

Saxena, Shalini; Abdullah, Maaged; Sriram, Dharmarajan; Guruprasad, Lalitha

2017-10-17

MurG (Rv2153c) is a key player in the biosynthesis of the peptidoglycan layer in Mycobacterium tuberculosis (Mtb). This work is an attempt to highlight the structural and functional relationship of Mtb MurG, the three-dimensional (3D) structure of protein was constructed by homology modelling using Discovery Studio 3.5 software. The quality and consistency of generated model was assessed by PROCHECK, ProSA and ERRAT. Later, the model was optimized by molecular dynamics (MD) simulations and the optimized model complex with substrate Uridine-diphosphate-N-acetylglucosamine (UD1) facilitated us to employ structure-based virtual screening approach to obtain new hits from Asinex database using energy-optimized pharmacophore modelling (e-pharmacophore). The pharmacophore model was validated using enrichment calculations, and finally, validated model was employed for high-throughput virtual screening and molecular docking to identify novel Mtb MurG inhibitors. This study led to the identification of 10 potential compounds with good fitness, docking score, which make important interactions with the protein active site. The 25 ns MD simulations of three potential lead compounds with protein confirmed that the structure was stable and make several non-bonding interactions with amino acids, such as Leu290, Met310 and Asn167. Hence, we concluded that the identified compounds may act as new leads for the design of Mtb MurG inhibitors.

Activation of a camptothecin prodrug by specific carboxylesterases as predicted by quantitative structure-activity relationship and molecular docking studies.

PubMed

Yoon, Kyoung Jin P; Krull, Erik J; Morton, Christopher L; Bornmann, William G; Lee, Richard E; Potter, Philip M; Danks, Mary K

2003-11-01

7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (irinotecan, CPT-11) is a camptothecin prodrug that is metabolized by carboxylesterases (CE) to the active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38), a topoisomerase I inhibitor. CPT-11 has shown encouraging antitumor activity against a broad spectrum of tumor types in early clinical trials, but hematopoietic and gastrointestinal toxicity limit its administration. To increase the therapeutic index of CPT-11 and to develop other prodrug analogues for enzyme/prodrug gene therapy applications, our laboratories propose to develop camptothecin prodrugs that will be activated by specific CEs. Specific analogues might then be predicted to be activated, for example, predominantly by human liver CE(hCE1), by human intestinal CE (hiCE), or in gene therapy approaches using a rabbit liver CE (rCE). This study describes a molecular modeling approach to relate the structure of rCE-activated camptothecin prodrugs with their biological activation. Comparative molecular field analysis, comparative molecular similarity index analysis, and docking studies were used to predict the biological activity of a 4-benzylpiperazine derivative of CPT-11 [7-ethyl-10-[4-(1-benzyl)-1-piperazino]carbonyloxycamptothecin (BP-CPT)] in U373MG glioma cell lines transfected with plasmids encoding rCE or hiCE. BP-CPT has been reported to be activated more efficiently than CPT-11 by a rat serum esterase activity; however, three-dimensional quantitative structure-activity relationship studies predicted that rCE would activate BP-CPT less efficiently than CPT-11. This was confirmed by both growth inhibition experiments and kinetic studies. The method is being used to design camptothecin prodrugs predicted to be activated by specific CEs.

Rapid Countermeasure Discovery against Francisella tularensis Based on a Metabolic Network Reconstruction

DTIC Science & Technology

2013-05-21

minimum inhibitory concentrations and mammalian cell cytotoxicities. The most promising compound had a low molecular weight, was non-toxic, and abolished... molecular weight, was non-toxic, and abolished bacterial growth at 13 mM, with putative activity against pantetheine-phosphate adenylyltransferase, an...time period. Metabolic genome-scale models of bacteria have provided a computational framework for in silico simulations to evaluate how metabolic

On the Dynamical Behavior of the Cysteine Dioxygenase-l-Cysteine Complex in the Presence of Free Dioxygen and l-Cysteine.

PubMed

Pietra, Francesco

2017-11-01

In this work, viable models of cysteine dioxygenase (CDO) and its complex with l-cysteine dianion were built for the first time, under strict adherence to the crystal structure from X-ray diffraction studies, for all atom molecular dynamics (MD). Based on the CHARMM36 FF, the active site, featuring an octahedral dummy Fe(II) model, allowed us observing water exchange, which would have escaped attention with the more popular bonded models. Free dioxygen (O 2 ) and l-cysteine, added at the active site, could be observed being expelled toward the solvating medium under Random Accelerated Molecular Dynamics (RAMD) along major and minor pathways. Correspondingly, free dioxygen (O 2 ), added to the solvating medium, could be observed to follow the same above pathways in getting to the active site under unbiased MD. For the bulky l-cysteine, 600 ns of trajectory were insufficient for protein penetration, and the molecule was stuck at the protein borders. These models pave the way to free energy studies of ligand associations, devised to better clarify how this cardinal enzyme behaves in human metabolism. © 2017 Wiley-VHCA AG, Zurich, Switzerland.

Synthetic oligosaccharides can replace animal-sourced low-molecular weight heparins.

PubMed

Xu, Yongmei; Chandarajoti, Kasemsiri; Zhang, Xing; Pagadala, Vijayakanth; Dou, Wenfang; Hoppensteadt, Debra Moorman; Sparkenbaugh, Erica M; Cooley, Brian; Daily, Sharon; Key, Nigel S; Severynse-Stevens, Diana; Fareed, Jawed; Linhardt, Robert J; Pawlinski, Rafal; Liu, Jian

2017-09-06

Low-molecular weight heparin (LMWH) is used clinically to treat clotting disorders. As an animal-sourced product, LMWH is a highly heterogeneous mixture, and its anticoagulant activity is not fully reversible by protamine. Furthermore, the reliability of the LMWH supply chain is a concern for regulatory agencies. We demonstrate the synthesis of heparin dodecasaccharides (12-mers) at the gram scale. In vitro experiments demonstrate that the anticoagulant activity of the 12-mers could be reversed using protamine. One of these, labeled as 12-mer-1, reduced the size of blood clots in the mouse model of deep vein thrombosis and attenuated circulating procoagulant markers in the mouse model of sickle cell disease. An ex vivo experiment demonstrates that the anticoagulant activity of 12-mer-1 could be reversed by protamine. 12-mer-1 was also examined in a nonhuman primate model to determine its pharmacodynamic parameters. A 7-day toxicity study in a rat model showed no toxic effects. The data suggest that a synthetic homogeneous oligosaccharide can replace animal-sourced LMWHs. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Molecular docking, molecular modeling, and molecular dynamics studies of azaisoflavone as dual COX-2 inhibitors and TP receptor antagonists.

PubMed

Hadianawala, Murtuza; Mahapatra, Amarjyoti Das; Yadav, Jitender K; Datta, Bhaskar

2018-02-26

Designed multi-target ligand (DML) is an emerging strategy for the development of new drugs and involves the engagement of multiple targets with the same moiety. In the context of NSAIDs it has been suggested that targeting the thromboxane prostanoid (TP) receptor along with cyclooxygenase-2 (COX-2) may help to overcome cardiovascular (CVS) complications associated with COXIBs. In the present work, azaisoflavones were studied for their COX-2 and TP receptor binding activities using structure based drug design (SBDD) techniques. Flavonoids were selected as a starting point based on their known COX-2 inhibitory and TP receptor antagonist activity. Iterative design and docking studies resulted in the evolution of a new class scaffold replacing the benzopyran-4-one ring of flavonoids with quinolin-4-one. The docking and binding parameters of these new compounds are found to be promising in comparison to those of selective COX-2 inhibitors, such as SC-558 and celecoxib. Owing to the lack of structural information, a model for the TP receptor was generated using a threading base alignment method with loop optimization performed using an ab initio method. The model generated was validated against known antagonists for TP receptor using docking/MMGBSA. Finally, the molecules that were designed for selective COX-2 inhibition were docked into the active site of the TP receptor. Iterative structural modifications and docking on these molecules generated a series which displays optimum docking scores and binding interaction for both targets. Molecular dynamics studies on a known TP receptor antagonist and a designed molecule show that both molecules remain in contact with protein throughout the simulation and interact in similar binding modes. Graphical abstract ᅟ.

Design and prediction of new acetylcholinesterase inhibitor via quantitative structure activity relationship of huprines derivatives.

PubMed

Zhang, Shuqun; Hou, Bo; Yang, Huaiyu; Zuo, Zhili

2016-05-01

Acetylcholinesterase (AChE) is an important enzyme in the pathogenesis of Alzheimer's disease (AD). Comparative quantitative structure-activity relationship (QSAR) analyses on some huprines inhibitors against AChE were carried out using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and hologram QSAR (HQSAR) methods. Three highly predictive QSAR models were constructed successfully based on the training set. The CoMFA, CoMSIA, and HQSAR models have values of r (2) = 0.988, q (2) = 0.757, ONC = 6; r (2) = 0.966, q (2) = 0.645, ONC = 5; and r (2) = 0.957, q (2) = 0.736, ONC = 6. The predictabilities were validated using an external test sets, and the predictive r (2) values obtained by the three models were 0.984, 0.973, and 0.783, respectively. The analysis was performed by combining the CoMFA and CoMSIA field distributions with the active sites of the AChE to further understand the vital interactions between huprines and the protease. On the basis of the QSAR study, 14 new potent molecules have been designed and six of them are predicted to be more active than the best active compound 24 described in the literature. The final QSAR models could be helpful in design and development of novel active AChE inhibitors.

Development of diabetes does not alter behavioral and molecular circadian rhythms in a transgenic rat model of type 2 diabetes mellitus.

PubMed

Qian, Jingyi; Thomas, Anthony P; Schroeder, Analyne M; Rakshit, Kuntol; Colwell, Christopher S; Matveyenko, Aleksey V

2017-08-01

Metabolic state and circadian clock function exhibit a complex bidirectional relationship. Circadian disruption increases propensity for metabolic dysfunction, whereas common metabolic disorders such as obesity and type 2 diabetes (T2DM) are associated with impaired circadian rhythms. Specifically, alterations in glucose availability and glucose metabolism have been shown to modulate clock gene expression and function in vitro; however, to date, it is unknown whether development of diabetes imparts deleterious effects on the suprachiasmatic nucleus (SCN) circadian clock and SCN-driven outputs in vivo. To address this question, we undertook studies in aged diabetic rats transgenic for human islet amyloid polypeptide, an established nonobese model of T2DM (HIP rat), which develops metabolic defects closely recapitulating those present in patients with T2DM. HIP rats were also cross-bred with a clock gene reporter rat model (Per1:luciferase transgenic rat) to permit assessment of the SCN and the peripheral molecular clock function ex vivo. Utilizing these animal models, we examined effects of diabetes on 1 ) behavioral circadian rhythms, 2 ) photic entrainment of circadian activity, 3 ) SCN and peripheral tissue molecular clock function, and 4 ) melatonin secretion. We report that circadian activity, light-induced entrainment, molecular clockwork, as well as melatonin secretion are preserved in the HIP rat model of T2DM. These results suggest that despite the well-characterized ability of glucose to modulate circadian clock gene expression acutely in vitro, SCN clock function and key behavioral and physiological outputs appear to be preserved under chronic diabetic conditions characteristic of nonobese T2DM. Copyright © 2017 the American Physiological Society.

Exploring possible mechanisms of action for the nanotoxicity and protein binding of decorated nanotubes: interpretation of physicochemical properties from optimal QSAR models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Esposito, Emilio Xavier, E-mail: emilio@exeResearch.com; The Chem21 Group, Inc., 1780 Wilson Drive, Lake Forest, IL 60045; Hopfinger, Anton J., E-mail: hopfingr@gmail.com

2015-10-01

Carbon nanotubes have become widely used in a variety of applications including biosensors and drug carriers. Therefore, the issue of carbon nanotube toxicity is increasingly an area of focus and concern. While previous studies have focused on the gross mechanisms of action relating to nanomaterials interacting with biological entities, this study proposes detailed mechanisms of action, relating to nanotoxicity, for a series of decorated (functionalized) carbon nanotube complexes based on previously reported QSAR models. Possible mechanisms of nanotoxicity for six endpoints (bovine serum albumin, carbonic anhydrase, chymotrypsin, hemoglobin along with cell viability and nitrogen oxide production) have been extracted frommore » the corresponding optimized QSAR models. The molecular features relevant to each of the endpoint respective mechanism of action for the decorated nanotubes are also discussed. Based on the molecular information contained within the optimal QSAR models for each nanotoxicity endpoint, either the decorator attached to the nanotube is directly responsible for the expression of a particular activity, irrespective of the decorator's 3D-geometry and independent of the nanotube, or those decorators having structures that place the functional groups of the decorators as far as possible from the nanotube surface most strongly influence the biological activity. These molecular descriptors are further used to hypothesize specific interactions involved in the expression of each of the six biological endpoints. - Highlights: • Proposed toxicity mechanism of action for decorated nanotubes complexes • Discussion of the key molecular features for each endpoint's mechanism of action • Unique mechanisms of action for each of the six biological systems • Hypothesized mechanisms of action based on QSAR/QNAR predictive models.« less

Molecular Characterization of Growth Hormone-producing Tumors in the GC Rat Model of Acromegaly.

PubMed

Martín-Rodríguez, Juan F; Muñoz-Bravo, Jose L; Ibañez-Costa, Alejandro; Fernandez-Maza, Laura; Balcerzyk, Marcin; Leal-Campanario, Rocío; Luque, Raúl M; Castaño, Justo P; Venegas-Moreno, Eva; Soto-Moreno, Alfonso; Leal-Cerro, Alfonso; Cano, David A

2015-11-09

Acromegaly is a disorder resulting from excessive production of growth hormone (GH) and consequent increase of insulin-like growth factor 1 (IGF-I), most frequently caused by pituitary adenomas. Elevated GH and IGF-I levels results in wide range of somatic, cardiovascular, endocrine, metabolic, and gastrointestinal morbidities. Subcutaneous implantation of the GH-secreting GC cell line in rats leads to the formation of tumors. GC tumor-bearing rats develop characteristics that resemble human acromegaly including gigantism and visceromegaly. However, GC tumors remain poorly characterized at a molecular level. In the present work, we report a detailed histological and molecular characterization of GC tumors using immunohistochemistry, molecular biology and imaging techniques. GC tumors display histopathological and molecular features of human GH-producing tumors, including hormone production, cell architecture, senescence activation and alterations in cell cycle gene expression. Furthermore, GC tumors cells displayed sensitivity to somatostatin analogues, drugs that are currently used in the treatment of human GH-producing adenomas, thus supporting the GC tumor model as a translational tool to evaluate therapeutic agents. The information obtained would help to maximize the usefulness of the GC rat model for research and preclinical studies in GH-secreting tumors.

Molecular Characterization of Growth Hormone-producing Tumors in the GC Rat Model of Acromegaly

PubMed Central

Martín-Rodríguez, Juan F.; Muñoz-Bravo, Jose L.; Ibañez-Costa, Alejandro; Fernandez-Maza, Laura; Balcerzyk, Marcin; Leal-Campanario, Rocío; Luque, Raúl M.; Castaño, Justo P.; Venegas-Moreno, Eva; Soto-Moreno, Alfonso; Leal-Cerro, Alfonso; Cano, David A.

2015-01-01

Acromegaly is a disorder resulting from excessive production of growth hormone (GH) and consequent increase of insulin-like growth factor 1 (IGF-I), most frequently caused by pituitary adenomas. Elevated GH and IGF-I levels results in wide range of somatic, cardiovascular, endocrine, metabolic, and gastrointestinal morbidities. Subcutaneous implantation of the GH-secreting GC cell line in rats leads to the formation of tumors. GC tumor-bearing rats develop characteristics that resemble human acromegaly including gigantism and visceromegaly. However, GC tumors remain poorly characterized at a molecular level. In the present work, we report a detailed histological and molecular characterization of GC tumors using immunohistochemistry, molecular biology and imaging techniques. GC tumors display histopathological and molecular features of human GH-producing tumors, including hormone production, cell architecture, senescence activation and alterations in cell cycle gene expression. Furthermore, GC tumors cells displayed sensitivity to somatostatin analogues, drugs that are currently used in the treatment of human GH-producing adenomas, thus supporting the GC tumor model as a translational tool to evaluate therapeutic agents. The information obtained would help to maximize the usefulness of the GC rat model for research and preclinical studies in GH-secreting tumors. PMID:26549306

Toxicity evaluation and prediction of toxic chemicals on activated sludge system.

PubMed

Cai, Bijing; Xie, Li; Yang, Dianhai; Arcangeli, Jean-Pierre

2010-05-15

The gaps of data for evaluating toxicity of new or overloaded organic chemicals on activated sludge system resulted in the requirements for methodology of toxicity estimation. In this study, 24 aromatic chemicals typically existed in the industrial wastewater were selected and classified into three groups of benzenes, phenols and anilines. Their toxicity on activated sludge was then investigated. Two indexes of IC(50-M) and IC(50-S) were determined respectively from the respiration rates of activated sludge with different toxicant concentration at mid-term (24h) and short-term (30min) time intervals. Experimental results showed that the group of benzenes was the most toxic, followed by the groups of phenols and anilines. The values of IC(50-M) of the tested chemicals were higher than those of IC(50-S). In addition, quantitative structure-activity relationships (QSARs) models developed from IC(50-M) were more stable and accurate than those of IC(50-S). The multiple linear models based on molecular descriptors and K(ow) presented better reliability than single linear models based on K(ow). Among these molecular descriptors, E(lumo) was the most important impact factor for evaluation of mid-term toxicity. Copyright (c) 2009 Elsevier B.V. All rights reserved.

Zebrafish knockout of Down syndrome gene, DYRK1A, shows social impairments relevant to autism.

PubMed

Kim, Oc-Hee; Cho, Hyun-Ju; Han, Enna; Hong, Ted Inpyo; Ariyasiri, Krishan; Choi, Jung-Hwa; Hwang, Kyu-Seok; Jeong, Yun-Mi; Yang, Se-Yeol; Yu, Kweon; Park, Doo-Sang; Oh, Hyun-Woo; Davis, Erica E; Schwartz, Charles E; Lee, Jeong-Soo; Kim, Hyung-Goo; Kim, Cheol-Hee

2017-01-01

DYRK1A maps to the Down syndrome critical region at 21q22. Mutations in this kinase-encoding gene have been reported to cause microcephaly associated with either intellectual disability or autism in humans. Intellectual disability accompanied by microcephaly was recapitulated in a murine model by overexpressing Dyrk1a which mimicked Down syndrome phenotypes. However, given embryonic lethality in homozygous knockout (KO) mice, no murine model studies could present sufficient evidence to link Dyrk1a dysfunction with autism. To understand the molecular mechanisms underlying microcephaly and autism spectrum disorders (ASD), we established an in vivo dyrk1aa KO model using zebrafish. We identified a patient with a mutation in the DYRK1A gene using microarray analysis. Circumventing the barrier of murine model studies, we generated a dyrk1aa KO zebrafish using transcription activator-like effector nuclease (TALEN)-mediated genome editing. For social behavioral tests, we have established a social interaction test, shoaling assay, and group behavior assay. For molecular analysis, we examined the neuronal activity in specific brain regions of dyrk1aa KO zebrafish through in situ hybridization with various probes including c-fos and crh which are the molecular markers for stress response. Microarray detected an intragenic microdeletion of DYRK1A in an individual with microcephaly and autism. From behavioral tests of social interaction and group behavior, dyrk1aa KO zebrafish exhibited social impairments that reproduce human phenotypes of autism in a vertebrate animal model. Social impairment in dyrk1aa KO zebrafish was further confirmed by molecular analysis of c-fos and crh expression. Transcriptional expression of c-fos and crh was lower than that of wild type fish in specific hypothalamic regions, suggesting that KO fish brains are less activated by social context. In this study, we established a zebrafish model to validate a candidate gene for autism in a vertebrate animal. These results illustrate the functional deficiency of DYRK1A as an underlying disease mechanism for autism. We also propose simple social behavioral assays as a tool for the broader study of autism candidate genes.

Structural insights into cholinesterases inhibition by harmane β-carbolinium derivatives: a kinetics-molecular modeling approach.

PubMed

Torres, Juliana M; Lira, Aline F; Silva, Daniel R; Guzzo, Lucas M; Sant'Anna, Carlos M R; Kümmerle, Arthur E; Rumjanek, Victor M

2012-09-01

The natural indole alkaloids, the β-carbolines, are often associated with cholinesterase inhibition, especially their quaternary salts, which frequently have higher activity than the free bases. Due to lack of information explaining this fact in the literature, the cholinesterase inhibition by the natural product harmane and its two β-carbolinium synthetic derivative salts (N-methyl and N-ethyl) was explored, together with a combination of kinetics and a molecular modeling approach. The results, mainly for the β-carbolinium salts, demonstrated a noncompetitive inhibition profile, ruling out previous findings which associated cholinesterase inhibition by β-carbolinium salts to a possible mimicking of the choline moiety of the natural substrate, acetylcholine. Molecular modeling studies corroborate this kind of inhibition through analyses of inhibitor/enzyme and inhibitor/substrate/enzyme complexes of both enzymes. Copyright © 2012 Elsevier Ltd. All rights reserved.

Is pigment patterning in fish skin determined by the Turing mechanism?

PubMed

Watanabe, Masakatsu; Kondo, Shigeru

2015-02-01

More than half a century ago, Alan Turing postulated that pigment patterns may arise from a mechanism that could be mathematically modeled based on the diffusion of two substances that interact with each other. Over the past 15 years, the molecular and genetic tools to verify this prediction have become available. Here, we review experimental studies aimed at identifying the mechanism underlying pigment pattern formation in zebrafish. Extensive molecular genetic studies in this model organism have revealed the interactions between the pigment cells that are responsible for the patterns. The mechanism discovered is substantially different from that predicted by the mathematical model, but it retains the property of 'local activation and long-range inhibition', a necessary condition for Turing pattern formation. Although some of the molecular details of pattern formation remain to be elucidated, current evidence confirms that the underlying mechanism is mathematically equivalent to the Turing mechanism. Copyright © 2014 Elsevier Ltd. All rights reserved.

Molecular modeling of NK-CT1, from Indian monocellate cobra (Naja kaouthia) and its docking interaction with human DNA topoisomerase II alpha

PubMed Central

Bandopadhyay, Pathikrit; Halder, Soma; Sarkar, Mrinmoy; Kumar Bhunia, Sujay; Dey, Sananda; Gomes, Antony; Giri, Biplab

2016-01-01

A 6.76 kDa molecular weight cardio and cytotoxic protein of 60 amino acids in length called NK-CT1, was purified from the venom of Indian monocellate cobra (Naja kaouthia) by ion-exchange chromatography and HPLC as described in our earlier report. Therefore it is of interest to utlize the sequence of NK-CT1 for further functional inference using molecular modeling and docking. Thus homology model of NK-CT1 is described in this report. The anti-proliferative activity of the protein, binding with human DNA topoisomerase-II alpha was demonstrated using docking data with AUTODOCK and AUTODOCK MGL tools. Data shows that M26, V27 and S28 of NK-CT1 is in close contact with the nucleotides of the oligonucleotide, bound with topoisomerase-II alpha complex. PMID:28149043

Predicting Monoamine Oxidase Inhibitory Activity through Ligand-Based Models

PubMed Central

Vilar, Santiago; Ferino, Giulio; Quezada, Elias; Santana, Lourdes; Friedman, Carol

2013-01-01

The evolution of bio- and cheminformatics associated with the development of specialized software and increasing computer power has produced a great interest in theoretical in silico methods applied in drug rational design. These techniques apply the concept that “similar molecules have similar biological properties” that has been exploited in Medicinal Chemistry for years to design new molecules with desirable pharmacological profiles. Ligand-based methods are not dependent on receptor structural data and take into account two and three-dimensional molecular properties to assess similarity of new compounds in regards to the set of molecules with the biological property under study. Depending on the complexity of the calculation, there are different types of ligand-based methods, such as QSAR (Quantitative Structure-Activity Relationship) with 2D and 3D descriptors, CoMFA (Comparative Molecular Field Analysis) or pharmacophoric approaches. This work provides a description of a series of ligand-based models applied in the prediction of the inhibitory activity of monoamine oxidase (MAO) enzymes. The controlled regulation of the enzymes’ function through the use of MAO inhibitors is used as a treatment in many psychiatric and neurological disorders, such as depression, anxiety, Alzheimer’s and Parkinson’s disease. For this reason, multiple scaffolds, such as substituted coumarins, indolylmethylamine or pyridazine derivatives were synthesized and assayed toward MAO-A and MAO-B inhibition. Our intention is to focus on the description of ligand-based models to provide new insights in the relationship between the MAO inhibitory activity and the molecular structure of the different inhibitors, and further study enzyme selectivity and possible mechanisms of action. PMID:23231398

Negative allosteric modulators that target human alpha4beta2 neuronal nicotinic receptors.

PubMed

Henderson, Brandon J; Pavlovicz, Ryan E; Allen, Jerad D; González-Cestari, Tatiana F; Orac, Crina M; Bonnell, Andrew B; Zhu, Michael X; Boyd, R Thomas; Li, Chenglong; Bergmeier, Stephen C; McKay, Dennis B

2010-09-01

Allosteric modulation of neuronal nicotinic acetylcholine receptors (nAChRs) is considered to be one of the most promising approaches for therapeutics. We have previously reported on the pharmacological activity of several compounds that act as negative allosteric modulators (NAMs) of nAChRs. In the following studies, the effects of 30 NAMs from our small chemical library on both human alpha4beta2 (Halpha4beta2) and human alpha3beta4 (Halpha3beta4) nAChRs expressed in human embryonic kidney ts201 cells were investigated. During calcium accumulation assays, these NAMs inhibited nAChR activation with IC(50) values ranging from 2.4 microM to more than 100 microM. Several NAMs showed relative selectivity for Halpha4beta2 nAChRs with IC(50) values in the low micromolar range. A lead molecule, KAB-18, was identified that shows relative selectivity for Halpha4beta2 nAChRs. This molecule contains three phenyl rings, one piperidine ring, and one ester bond linkage. Structure-activity relationship (SAR) analyses of our data revealed three regions of KAB-18 that contribute to its relative selectivity. Predictive three-dimensional quantitative SAR (comparative molecular field analysis and comparative molecular similarity indices analysis) models were generated from these data, and a pharmacophore model was constructed to determine the chemical features that are important for biological activity. Using docking approaches and molecular dynamics on a Halpha4beta2 nAChR homology model, a binding mode for KAB-18 at the alpha/beta subunit interface that corresponds to the predicted pharmacophore is described. This binding mode was supported by mutagenesis studies. In summary, these studies highlight the importance of SAR, computational, and molecular biology approaches for the design and synthesis of potent and selective antagonists targeting specific nAChR subtypes.

Negative Allosteric Modulators That Target Human α4β2 Neuronal Nicotinic Receptors

PubMed Central

Henderson, Brandon J.; Pavlovicz, Ryan E.; Allen, Jerad D.; González-Cestari, Tatiana F.; Orac, Crina M.; Bonnell, Andrew B.; Zhu, Michael X.; Boyd, R. Thomas; Li, Chenglong; Bergmeier, Stephen C.

2010-01-01

Allosteric modulation of neuronal nicotinic acetylcholine receptors (nAChRs) is considered to be one of the most promising approaches for therapeutics. We have previously reported on the pharmacological activity of several compounds that act as negative allosteric modulators (NAMs) of nAChRs. In the following studies, the effects of 30 NAMs from our small chemical library on both human α4β2 (Hα4β2) and human α3β4 (Hα3β4) nAChRs expressed in human embryonic kidney ts201 cells were investigated. During calcium accumulation assays, these NAMs inhibited nAChR activation with IC50 values ranging from 2.4 μM to more than 100 μM. Several NAMs showed relative selectivity for Hα4β2 nAChRs with IC50 values in the low micromolar range. A lead molecule, KAB-18, was identified that shows relative selectivity for Hα4β2 nAChRs. This molecule contains three phenyl rings, one piperidine ring, and one ester bond linkage. Structure–activity relationship (SAR) analyses of our data revealed three regions of KAB-18 that contribute to its relative selectivity. Predictive three-dimensional quantitative SAR (comparative molecular field analysis and comparative molecular similarity indices analysis) models were generated from these data, and a pharmacophore model was constructed to determine the chemical features that are important for biological activity. Using docking approaches and molecular dynamics on a Hα4β2 nAChR homology model, a binding mode for KAB-18 at the α/β subunit interface that corresponds to the predicted pharmacophore is described. This binding mode was supported by mutagenesis studies. In summary, these studies highlight the importance of SAR, computational, and molecular biology approaches for the design and synthesis of potent and selective antagonists targeting specific nAChR subtypes. PMID:20551292

Orientation to determine quality attributes of flavoring excipients containing volatile molecules.

PubMed

Kiene, Florian E; Pein, Miriam; Thommes, Markus

2015-06-10

Pharmaceutical excipients containing volatile odor-active molecules can be used in pharmaceutical development to increase patients' compliance. However, capturing the molecular composition of these odor-active substances is challenging. Therefore, guidance for the analytical investigation of these excipients should be developed. Using a model flavor, lead molecules were chosen and a gas chromatographic method was validated according to pharmaceutical guidelines. Changes during storage as well as batch homogeneity and conformity were investigated. The knowledge gained could be used to understand molecular differences between batches caused by aging. A suitable attempt to capture the volatile molecular composition of flavoring substance was presented and the found results could be used for the determination and interpretation of quality attributes. Copyright © 2015 Elsevier B.V. All rights reserved.

Molecular surface area based predictive models for the adsorption and diffusion of disperse dyes in polylactic acid matrix.

PubMed

Xu, Suxin; Chen, Jiangang; Wang, Bijia; Yang, Yiqi

2015-11-15

Two predictive models were presented for the adsorption affinities and diffusion coefficients of disperse dyes in polylactic acid matrix. Quantitative structure-sorption behavior relationship would not only provide insights into sorption process, but also enable rational engineering for desired properties. The thermodynamic and kinetic parameters for three disperse dyes were measured. The predictive model for adsorption affinity was based on two linear relationships derived by interpreting the experimental measurements with molecular structural parameters and compensation effect: ΔH° vs. dye size and ΔS° vs. ΔH°. Similarly, the predictive model for diffusion coefficient was based on two derived linear relationships: activation energy of diffusion vs. dye size and logarithm of pre-exponential factor vs. activation energy of diffusion. The only required parameters for both models are temperature and solvent accessible surface area of the dye molecule. These two predictive models were validated by testing the adsorption and diffusion properties of new disperse dyes. The models offer fairly good predictive ability. The linkage between structural parameter of disperse dyes and sorption behaviors might be generalized and extended to other similar polymer-penetrant systems. Copyright © 2015 Elsevier Inc. All rights reserved.

Interpretation of pH-activity profiles for acid-base catalysis from molecular simulations.

PubMed

Dissanayake, Thakshila; Swails, Jason M; Harris, Michael E; Roitberg, Adrian E; York, Darrin M

2015-02-17

The measurement of reaction rate as a function of pH provides essential information about mechanism. These rates are sensitive to the pK(a) values of amino acids directly involved in catalysis that are often shifted by the enzyme active site environment. Experimentally observed pH-rate profiles are usually interpreted using simple kinetic models that allow estimation of "apparent pK(a)" values of presumed general acid and base catalysts. One of the underlying assumptions in these models is that the protonation states are uncorrelated. In this work, we introduce the use of constant pH molecular dynamics simulations in explicit solvent (CpHMD) with replica exchange in the pH-dimension (pH-REMD) as a tool to aid in the interpretation of pH-activity data of enzymes and to test the validity of different kinetic models. We apply the methods to RNase A, a prototype acid-base catalyst, to predict the macroscopic and microscopic pK(a) values, as well as the shape of the pH-rate profile. Results for apo and cCMP-bound RNase A agree well with available experimental data and suggest that deprotonation of the general acid and protonation of the general base are not strongly coupled in transphosphorylation and hydrolysis steps. Stronger coupling, however, is predicted for the Lys41 and His119 protonation states in apo RNase A, leading to the requirement for a microscopic kinetic model. This type of analysis may be important for other catalytic systems where the active forms of the implicated general acid and base are oppositely charged and more highly correlated. These results suggest a new way for CpHMD/pH-REMD simulations to bridge the gap with experiments to provide a molecular-level interpretation of pH-activity data in studies of enzyme mechanisms.

Interpretation of pH-activity Profiles for Acid-Base Catalysis from Molecular Simulations

PubMed Central

Dissanayake, Thakshila; Swails, Jason; Harris, Michael E.; Roitberg, Adrian E.; York, Darrin M.

2015-01-01

The measurement of reaction rate as a function of pH provides essential information about mechanism. These rates are sensitive to the pKa values of amino acids directly involved in catalysis that are often shifted by the enzyme active site environment. Experimentally observed pH-rate profiles are usually interpreted using simple kinetic models that allow estimation of “apparent pKa” values of presumed general acid and base catalysts. One of the underlying assumptions in these models is that the protonation states are uncorrelated. In the present work, we introduce the use of constant pH molecular dynamics simulations in explicit solvent (CpHMD) with replica exchange in the pH-dimension (pH-REMD) as a tool to aid in the interpretation of pH-activity data of enzymes, and test the validity of different kinetic models. We apply the methods to RNase A, a prototype acid/base catalyst, to predict the macroscopic and microscopic pKa values, as well as the shape of the pH-rate profile. Results for apo and cCMP-bound RNase A agree well with available experimental data, and suggest that deprotonation of the general acid and protonation of the general base are not strongly coupled in transphosphorylation and hydrolysis steps. Stronger coupling, however, is predicted for the Lys41 and His119 protonation states in apo RNase A, leading to the requirement for a microscopic kinetic model. This type of analysis may be important for other catalytic systems where the active forms of implicated general acid and base are oppositely charged and more highly correlated. These results suggest a new way for CpHMD/pH-REMD simulations to bridge the gap with experiments to provide a molecular-level interpretation of pH-activity data in studies of enzyme mechanisms. PMID:25615525

An "ex vivo model" contributing to the diagnosis and evaluation of new drugs in cystic fibrosis.

PubMed

Di Lullo, A M; Scorza, M; Amato, F; Comegna, M; Raia, V; Maiuri, L; Ilardi, G; Cantone, E; Castaldo, G; Iengo, M

2017-06-01

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene. About 2000 mutations have been described so far. We setup an ex vivo model of human nasal epithelial cells (HNECs) to study CF patients testing the effect of novel mutations and molecular therapies. We performed sampling (by brushing), followed by culture and analysis of HNECs using a series of molecular techniques. We performed 50 brushings from CF patients and controls. Using cultured cells, we: i) demonstrated the widely heterogeneous CFTR expression in patients and in controls; ii) defined the splicing effect of a CFTR mutation; iii) assessed the CFTR gating activity in patients bearing different mutations; iv) demonstrated that butyrate significantly enhances CFTR expression. Based on our data, we can conclude: 1) HNEC brushing is performed without anaesthesia and is well tolerated in all CF patients (children and adults); 2) HNECs can be preserved for up to 48 hours before culture allowings multicentre studies; 3) HNECs culture can be considered a suitable model to study the molecular effects of new CFTR gene mutations and/or uncertain meaning specific mutations of carriers; 4) an ex vivo model of HNECs may be used to evaluate, before human use, the effect of new drugs on patients' cells bearing specific CFTR mutations; 5) the methodology is adequate for a quantitative measurement, by fluorescence, of the CFTR gating activity of the HNECs from patients with different genotypes identifying: a) CF patients bearing two severe mutations with an activity < 10% (compared to controls - 100%); b) CF patients bearing at least a mild mutation with an activity of 10-20%; c) CF carriers (heterozygous subjects) with an activity between 40-70%. © Copyright by Società Italiana di Otorinolaringologia e Chirurgia Cervico-Facciale, Rome, Italy.

Design new P-glycoprotein modulators based on molecular docking and CoMFA study of α, β-unsaturated carbonyl-based compounds and oxime analogs as anticancer agents

NASA Astrophysics Data System (ADS)

Sepehri, Bakhtyar; Ghavami, Raouf

2017-02-01

In this research, molecular docking and CoMFA were used to determine interactions of α, β-unsaturated carbonyl-based compounds and oxime analogs with P-glycoprotein and prediction of their activity. Molecular docking study shown these molecules establish strong Van der Waals interactions with side chain of PHE-332, PHE-728 and PHE-974. Based on the effect of component numbers on squared correlation coefficient for cross validation tests (including leave-one-out and leave-many-out), CoMFA models with five components were built to predict pIC50 of molecules in seven cancer cell lines (including Panc-1 (pancreas cancer cell line), PaCa-2 (pancreatic carcinoma cell line), MCF-7 (breast cancer cell line), A-549 (epithelial), HT-29 (colon cancer cell line), H-460 (lung cancer cell line), PC-3 (prostate cancer cell line)). R2 values for training and test sets were in the range of 0.94-0.97 and 0.84 to 0.92, respectively, and for LOO and LMO cross validation test, q2 values were in the range of 0.75-0.82 and 0.65 to 0.73, respectively. Based on molecular docking results and extracted steric and electrostatic contour maps for CoMFA models, four new molecules with higher activity with respect to the most active compound in data set were designed.

In silico design of anti-atherogenic biomaterials.

PubMed

Lewis, Daniel R; Kholodovych, Vladyslav; Tomasini, Michael D; Abdelhamid, Dalia; Petersen, Latrisha K; Welsh, William J; Uhrich, Kathryn E; Moghe, Prabhas V

2013-10-01

Atherogenesis, the uncontrolled deposition of modified lipoproteins in inflamed arteries, serves as a focal trigger of cardiovascular disease (CVD). Polymeric biomaterials have been envisioned to counteract atherogenesis based on their ability to repress scavenger mediated uptake of oxidized lipoprotein (oxLDL) in macrophages. Following the conceptualization in our laboratories of a new library of amphiphilic macromolecules (AMs), assembled from sugar backbones, aliphatic chains and poly(ethylene glycol) tails, a more rational approach is necessary to parse the diverse features such as charge, hydrophobicity, sugar composition and stereochemistry. In this study, we advance a computational biomaterials design approach to screen and elucidate anti-atherogenic biomaterials with high efficacy. AMs were quantified in terms of not only 1D (molecular formula) and 2D (molecular connectivity) descriptors, but also new 3D (molecular geometry) descriptors of AMs modeled by coarse-grained molecular dynamics (MD) followed by all-atom MD simulations. Quantitative structure-activity relationship (QSAR) models for anti-atherogenic activity were then constructed by screening a total of 1164 descriptors against the corresponding, experimentally measured potency of AM inhibition of oxLDL uptake in human monocyte-derived macrophages. Five key descriptors were identified to provide a strong linear correlation between the predicted and observed anti-atherogenic activity values, and were then used to correctly forecast the efficacy of three newly designed AMs. Thus, a new ligand-based drug design framework was successfully adapted to computationally screen and design biomaterials with cardiovascular therapeutic properties. Copyright © 2013 Elsevier Ltd. All rights reserved.

NMR signal enhancement by effective SABRE labeling of oligopeptides.

PubMed

Ratajczyk, Tomasz; Gutmann, Torsten; Bernatowicz, Piotr; Buntkowsky, Gerd; Frydel, Jaroslaw; Fedorczyk, Bartlomiej

2015-09-01

Signal amplification by reversible exchange (SABRE) can enhance nuclear magnetic resonance signals by several orders of magnitude. However, until now this was limited to a small number of model target molecules. Here, a new convenient method for SABRE activation applicable to a variety of synthetic model oligopeptides is demonstrated. For the first time, a highly SABRE-active pyridine-based biocompatible molecular framework is incorporated into synthetic oligopeptides. The SABRE activity is preserved, demonstrating the importance of such earmarking. Finally, a crucial exchange process responsible for SABRE activity is identified and discussed. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Student construction of small molecule models using Spartan Model to explore polarity

NASA Astrophysics Data System (ADS)

Dale, Glenn Lamar

2006-12-01

This study compared the attitudes and the gains of knowledge concerning Lewis structures and polarity of molecules. The students performed a lab exercise in which they drew Lewis structures, constructed models of the molecules, determined the geometry of the molecules, and determined the polarity of the molecules. The control group students constructed models using physical ball-and-stick models. The treatment group students used Spartan Model to construct models. Students from a university and a community college participated in this study. Four lab classes at each school made up the treatment group. Five lab classes at the university and three lab classes at the community college made up the control group. The treatment group classes were selected based on available computer resources. All students in the study were given the Lab Pre Test, Lab Post Test, and the Lecture Post Test to assess the student's ability to answer questions pertaining to Lewis structures and polarity of molecules. An Attitudinal Survey assessed the attitudes of the students who participated in the study. Student interviews were performed to assess the student's attitudes towards the lab exercise. The interviews investigated attitudes about the modeling exercise, Lewis structures, and polarity of molecules. There were no significant differences in the performance of the treatment group when compared to the control group on the performance assessment instruments at the university or the community college. The treatment group students at the university had a more positive attitude about the lab activity. They believed that the lab activity helped them better understand the concepts of Lewis structure and molecular polarity. At the community college, the control group students had a more positive attitude about the lab activity. The students involved in the study believed that the lab activity helped them to understand the concepts of molecular geometry and polarity. The interviews of the treatment group students indicated that they strongly believed that the lab activity helped them better understand the concept of Lewis structures and of molecular polarity. As reflected in the interviews of the treatment group and the control group, the lab activity did not help the students be able to look at a Lewis structure and build a mental image of the molecule. The students believed the electrostatic potential plots generated by Spartan Model were very insightful into the concept of polarity. It gave them a visual representation of a difficult topic.

A new predictive model for the bioconcentration factors of polychlorinated biphenyls (PCBs) based on the molecular electronegativity distance vector (MEDV).

PubMed

Qin, Li-Tang; Liu, Shu-Shen; Liu, Hai-Ling; Ge, Hui-Lin

2008-02-01

Polychlorinated biphenyls (PCBs) are some of the most prevalent pollutants in the total environment and receive more and more concerns as a group of ubiquitous potential persistent organic pollutants. Using the variable selection and modeling based on prediction (VSMP), the molecular electronegativity distance vector (MEDV) derived directly from the molecular topological structures was employed to develop a linear model (MI) between the bioconcentration factors (BCF) and two MEDV descriptors of 58 PCBs. The MI model showed a good estimation ability with a correlation coefficient (r) of 0.9605 and a high stability with a leave-one-out cross-validation correlation coefficient (q) of 0.9564. The MEDV-base model (MI) is easier to use than the splinoid poset method reported by Ivanciuc et al. [Ivanciuc, T., Ivanciuc, O., Klein, D.J., 2006. Modeling the bioconcentration factors and bioaccumulation factors of polychlorinated biphenyls with posetic quatitative super-structure/activity relationships (QSSAR). Mol. Divers. 10, 133-145] and gives a better statistics than molecular connectivity index (MCI)-base model developed by Hu et al. [Hu, H.Y., Xu, F.L., Li, B.G., Cao, J., Dawson, R., Tao, S., 2005. Prediction of the bioconcentration factor of PCBs in fish using the molecular connectivity index and fragment constant models. Water Environ. Res. 77, 87-97]. Main structural factors influencing the BCF of PCBs are the substructures expressed by two atomic groups >C= and -CH=. 58 PCBs were divided into an "odd set" and "even set" in order to ensure the predicted potential of the MI for the external samples. It was shown that three models, MI, MO for "odd set", and ME for "even set", can be used to predict the BCF of remaining 152 PCBs in which the experimental BCFs are not available.

Conformational analysis of GT1B ganglioside and its interaction with botulinum neurotoxin type B: a study by molecular modeling and molecular dynamics.

PubMed

Venkateshwari, Sureshkumar; Veluraja, Kasinadar

2012-01-01

The conformational property of oligosaccharide GT1B in aqueous environment was studied by molecular dynamics (MD) simulation using all-atom model. Based on the trajectory analysis, three prominent conformational models were proposed for GT1B. Direct and water-mediated hydrogen bonding interactions stabilize these structures. The molecular modeling and 15 ns MD simulation of the Botulinum Neuro Toxin/B (BoNT/B) - GT1B complex revealed that BoNT/B can accommodate the GT1B in the single binding mode. Least mobility was seen for oligo-GT1B in the binding pocket. The bound conformation of GT1B obtained from the MD simulation of the BoNT/B-GT1B complex bear a close conformational similarity with the crystal structure of BoNT/A-GT1B complex. The mobility noticed for Arg 1268 in the dynamics was accounted for its favorable interaction with terminal NeuNAc. The internal NeuNAc1 tends to form 10 hydrogen bonds with BoNT/B, hence specifying this particular site as a crucial space for the therapeutic design that can restrict the pathogenic activity of BoNT/B.

Visualizing the phage T4 activated transcription complex of DNA and E. coli RNA polymerase

PubMed Central

James, Tamara D.; Cardozo, Timothy; Abell, Lauren E.; Hsieh, Meng-Lun; Jenkins, Lisa M. Miller; Jha, Saheli S.; Hinton, Deborah M.

2016-01-01

The ability of RNA polymerase (RNAP) to select the right promoter sequence at the right time is fundamental to the control of gene expression in all organisms. However, there is only one crystallized structure of a complete activator/RNAP/DNA complex. In a process called σ appropriation, bacteriophage T4 activates a class of phage promoters using an activator (MotA) and a co-activator (AsiA), which function through interactions with the σ70 subunit of RNAP. We have developed a holistic, structure-based model for σ appropriation using multiple experimentally determined 3D structures (Escherichia coli RNAP, the Thermus aquaticus RNAP/DNA complex, AsiA /σ70 Region 4, the N-terminal domain of MotA [MotANTD], and the C-terminal domain of MotA [MotACTD]), molecular modeling, and extensive biochemical observations indicating the position of the proteins relative to each other and to the DNA. Our results visualize how AsiA/MotA redirects σ, and therefore RNAP activity, to T4 promoter DNA, and demonstrate at a molecular level how the tactful interaction of transcriptional factors with even small segments of RNAP can alter promoter specificity. Furthermore, our model provides a rational basis for understanding how a mutation within the β subunit of RNAP (G1249D), which is far removed from AsiA or MotA, impairs σ appropriation. PMID:27458207

Generic Transport Mechanisms for Molecular Traffic in Cellular Protrusions

NASA Astrophysics Data System (ADS)

Graf, Isabella R.; Frey, Erwin

2017-03-01

Transport of molecular motors along protein filaments in a half-closed geometry is a common feature of biologically relevant processes in cellular protrusions. Using a lattice-gas model we study how the interplay between active and diffusive transport and mass conservation leads to localized domain walls and tip localization of the motors. We identify a mechanism for task sharing between the active motors (maintaining a gradient) and the diffusive motion (transport to the tip), which ensures that energy consumption is low and motor exchange mostly happens at the tip. These features are attributed to strong nearest-neighbor correlations that lead to a strong reduction of active currents, which we calculate analytically using an exact moment identity, and might prove useful for the understanding of correlations and active transport also in more elaborate systems.

Edible bioactive fatty acid-cellulosic derivative composites used in food-packaging applications.

PubMed

Sebti, Issam; Ham-Pichavant, Frédérique; Coma, Véronique

2002-07-17

To develop biodegradable packaging that both acts as a moisture barrier and as antimicrobial activity, nisin and stearic acid were incorporated into a hydroxy propyl methyl cellulose (HPMC) based film. Fifteen percent (w/w HPMC) of stearic acid improved film moisture barrier. However, film mechanical resistance and film antimicrobial activity on Listeria monocytogenes and Staphylococcus aureus pathogenic strains were both reduced. This lower film inhibitory activity was due to interactions between nisin and stearic acid. The molecular interaction was modeled, and an equation was developed to calculate the nisin concentration needed to be incorporated into the film matrix to obtain a desired residual antimicrobial activity. Because the molecular interactions were pH dependent, the impact of the pH of the film-forming solution on film inhibitory activity was investigated. Adjusting the pH to 3 totally avoided stearic acid and nisin interaction, inducing a high film inhibitory activity.

Competing dynamic phases of active polymer networks

NASA Astrophysics Data System (ADS)

Freedman, Simon; Banerjee, Shiladitya; Dinner, Aaron R.

Recent experiments on in-vitro reconstituted assemblies of F-actin, myosin-II motors, and cross-linking proteins show that tuning local network properties can changes the fundamental biomechanical behavior of the system. For example, by varying cross-linker density and actin bundle rigidity, one can switch between contractile networks useful for reshaping cells, polarity sorted networks ideal for directed molecular transport, and frustrated networks with robust structural properties. To efficiently investigate the dynamic phases of actomyosin networks, we developed a coarse grained non-equilibrium molecular dynamics simulation of model semiflexible filaments, molecular motors, and cross-linkers with phenomenologically defined interactions. The simulation's accuracy was verified by benchmarking the mechanical properties of its individual components and collective behavior against experimental results at the molecular and network scales. By adjusting the model's parameters, we can reproduce the qualitative phases observed in experiment and predict the protein characteristics where phase crossovers could occur in collective network dynamics. Our model provides a framework for understanding cells' multiple uses of actomyosin networks and their applicability in materials research. Supported by the Department of Defense (DoD) through the National Defense Science & Engineering Graduate Fellowship (NDSEG) Program.

Kinetic Analysis of a Molecular Model of the Budding Yeast Cell Cycle

PubMed Central

Chen, Katherine C.; Csikasz-Nagy, Attila; Gyorffy, Bela; Val, John; Novak, Bela; Tyson, John J.

2000-01-01

The molecular machinery of cell cycle control is known in more detail for budding yeast, Saccharomyces cerevisiae, than for any other eukaryotic organism. In recent years, many elegant experiments on budding yeast have dissected the roles of cyclin molecules (Cln1–3 and Clb1–6) in coordinating the events of DNA synthesis, bud emergence, spindle formation, nuclear division, and cell separation. These experimental clues suggest a mechanism for the principal molecular interactions controlling cyclin synthesis and degradation. Using standard techniques of biochemical kinetics, we convert the mechanism into a set of differential equations, which describe the time courses of three major classes of cyclin-dependent kinase activities. Model in hand, we examine the molecular events controlling “Start” (the commitment step to a new round of chromosome replication, bud formation, and mitosis) and “Finish” (the transition from metaphase to anaphase, when sister chromatids are pulled apart and the bud separates from the mother cell) in wild-type cells and 50 mutants. The model accounts for many details of the physiology, biochemistry, and genetics of cell cycle control in budding yeast. PMID:10637314

Structure of pleiotrophin- and hepatocyte growth factor-binding sulfated hexasaccharide determined by biochemical and computational approaches.

PubMed

Li, Fuchuan; Nandini, Chilkunda D; Hattori, Tomohide; Bao, Xingfeng; Murayama, Daisuke; Nakamura, Toshikazu; Fukushima, Nobuhiro; Sugahara, Kazuyuki

2010-09-03

Endogenous pleiotrophin and hepatocyte growth factor (HGF) mediate the neurite outgrowth-promoting activity of chondroitin sulfate (CS)/dermatan sulfate (DS) hybrid chains isolated from embryonic pig brain. CS/DS hybrid chains isolated from shark skin have a different disaccharide composition, but also display these activities. In this study, pleiotrophin- and HGF-binding domains in shark skin CS/DS were investigated. A high affinity CS/DS fraction was isolated using a pleiotrophin-immobilized column. It showed marked neurite outgrowth-promoting activity and strong inhibitory activity against the binding of pleiotrophin to immobilized CS/DS chains from embryonic pig brain. The inhibitory activity was abolished by chondroitinase ABC or B, and partially reduced by chondroitinase AC-I. A pentasulfated hexasaccharide with a novel structure was isolated from the chondroitinase AC-I digest using pleiotrophin affinity and anion exchange chromatographies. It displayed a potent inhibitory effect on the binding of HGF to immobilized shark skin CS/DS chains, suggesting that the pleiotrophin- and HGF-binding domains at least partially overlap in the CS/DS chains involved in the neuritogenic activity. Computational chemistry using molecular modeling and calculations of the electrostatic potential of the hexasaccharide and two pleiotrophin-binding octasaccharides previously isolated from CS/DS hybrid chains of embryonic pig brain identified an electronegative zone potentially involved in the molecular recognition of the oligosaccharides by pleiotrophin. Homology modeling of pleiotrophin based on a related midkine protein structure predicted the binding pocket of pleiotrophin for the oligosaccharides and provided new insights into the molecular mechanism of the interactions between the oligosaccharides and pleiotrophin.

Stress-induced mutation via DNA breaks in Escherichia coli: A molecular mechanism with implications for evolution and medicine

PubMed Central

Rosenberg, Susan M; Shee, Chandan; Frisch, Ryan L; Hastings, P J

2012-01-01

Abstract Evolutionary theory assumed that mutations occur constantly, gradually, and randomly over time. This formulation from the “modern synthesis” of the 1930s was embraced decades before molecular understanding of genes or mutations. Since then, our labs and others have elucidated mutation mechanisms activated by stress responses. Stress-induced mutation mechanisms produce mutations, potentially accelerating evolution, specifically when cells are maladapted to their environment, that is, when they are stressed. The mechanisms of stress-induced mutation that are being revealed experimentally in laboratory settings provide compelling models for mutagenesis that propels pathogen–host adaptation, antibiotic resistance, cancer progression and resistance, and perhaps much of evolution generally. We discuss double-strand-break-dependent stress-induced mutation in Escherichia coli. Recent results illustrate how a stress response activates mutagenesis and demonstrate this mechanism's generality and importance to spontaneous mutation. New data also suggest a possible harmony between previous, apparently opposed, models for the molecular mechanism. They additionally strengthen the case for anti-evolvability therapeutics for infectious disease and cancer. PMID:22911060

Stress-induced mutation via DNA breaks in Escherichia coli: a molecular mechanism with implications for evolution and medicine.

PubMed

Rosenberg, Susan M; Shee, Chandan; Frisch, Ryan L; Hastings, P J

2012-10-01

Evolutionary theory assumed that mutations occur constantly, gradually, and randomly over time. This formulation from the "modern synthesis" of the 1930s was embraced decades before molecular understanding of genes or mutations. Since then, our labs and others have elucidated mutation mechanisms activated by stress responses. Stress-induced mutation mechanisms produce mutations, potentially accelerating evolution, specifically when cells are maladapted to their environment, that is, when they are stressed. The mechanisms of stress-induced mutation that are being revealed experimentally in laboratory settings provide compelling models for mutagenesis that propels pathogen-host adaptation, antibiotic resistance, cancer progression and resistance, and perhaps much of evolution generally. We discuss double-strand-break-dependent stress-induced mutation in Escherichia coli. Recent results illustrate how a stress response activates mutagenesis and demonstrate this mechanism's generality and importance to spontaneous mutation. New data also suggest a possible harmony between previous, apparently opposed, models for the molecular mechanism. They additionally strengthen the case for anti-evolvability therapeutics for infectious disease and cancer. Copyright © 2012 WILEY Periodicals, Inc.

Facile synthesis, biological evaluation and molecular docking studies of novel substituted azole derivatives

NASA Astrophysics Data System (ADS)

Rafiq, Muhammad; Saleem, Muhammad; Jabeen, Farukh; Hanif, Muhammad; Seo, Sung-Yum; Kang, Sung Kwon; Lee, Ki Hwan

2017-06-01

In this study, we synthesized the series of novel azole derivatives and evaluated for enzyme inhibition assays, corresponding kinetic analysis and molecular modeling. Among the investigated bioassays, the oxadiazole derivatives 4a-k were found potent α-glucosidase inhibitors while the Schiff base derivatives 7a-k exhibited considerable potential toward urease inhibition. The inhibition kinetics for the most active compounds were analyzed by the Lineweaver-Burk plots to investigate the possible binding modes of the synthesized compounds toward the tested proteins. Moreover, the detailed docking studies were performed on the synthesized library of 4a-k and 7a-k to study the molecular interaction and binding mode in the active site of the modeled yeast α-glucosidase and Jack Bean Urease, respectively. It could be inferred from docking results that theoretical studies are in close agreement to that of the experimental results. The structure of one of the compound 7k was characterized by the single crystal X-ray diffraction analysis in order to find out the predominant conformation of the molecules.

Physiological controls of large‐scale patterning in planarian regeneration: a molecular and computational perspective on growth and form

PubMed Central

Durant, Fallon; Lobo, Daniel; Hammelman, Jennifer

2016-01-01

Abstract Planaria are complex metazoans that repair damage to their bodies and cease remodeling when a correct anatomy has been achieved. This model system offers a unique opportunity to understand how large‐scale anatomical homeostasis emerges from the activities of individual cells. Much progress has been made on the molecular genetics of stem cell activity in planaria. However, recent data also indicate that the global pattern is regulated by physiological circuits composed of ionic and neurotransmitter signaling. Here, we overview the multi‐scale problem of understanding pattern regulation in planaria, with specific focus on bioelectric signaling via ion channels and gap junctions (electrical synapses), and computational efforts to extract explanatory models from functional and molecular data on regeneration. We present a perspective that interprets results in this fascinating field using concepts from dynamical systems theory and computational neuroscience. Serving as a tractable nexus between genetic, physiological, and computational approaches to pattern regulation, planarian pattern homeostasis harbors many deep insights for regenerative medicine, evolutionary biology, and engineering. PMID:27499881

The catalytic activity for ginkgolic acid biodegradation, homology modeling and molecular dynamic simulation of salicylic acid decarboxylase.

PubMed

Hu, Yanying; Hua, Qingyuan; Sun, Guojuan; Shi, Kunpeng; Zhang, Huitu; Zhao, Kai; Jia, Shiru; Dai, Yujie; Wu, Qingli

2018-05-02

The toxic ginkgolic acids are the main safety concern for the application of Ginkgo biloba. In this study, the degradation ability of salicylic acid decarboxylase (SDC) for ginkgolic acids was examined using ginkgolic acid C15:1 as a substrate. The results indicated that the content of ginkgolic acid C15:1 in Ginkgo biloba seeds was significantly decreased after 5 h treatment with SDC at 40 °Cand pH 5.5. In order to explore the structure of SDC and the interaction between SDC and substrates, homology modeling, molecular docking and molecular dynamics were performed. The results showed that SDC might also have a catalytic active center containing a Zn 2+ . Compared with the template structure of 2,6-dihydroxybenzoate decarboxylase, the residues surrounding the binding pocket, His10, Phe23 and Phe290, were replaced by Ala10, Tyr27 and Tyr301 in the homology constructed structure of SDC, respectively. These differences may significantly affect the substrates adaptability of SDC for salicylic acid derivatives. Copyright © 2018 Elsevier Ltd. All rights reserved.

Insight into a novel p53 single point mutation (G389E) by Molecular Dynamics Simulations.

PubMed

Pirolli, Davide; Carelli Alinovi, Cristiana; Capoluongo, Ettore; Satta, Maria Antonia; Concolino, Paola; Giardina, Bruno; De Rosa, Maria Cristina

2010-12-30

The majority of inactivating mutations of p53 reside in the central core DNA binding domain of the protein. In this computational study, we investigated the structural effects of a novel p53 mutation (G389E), identified in a patient with congenital adrenal hyperplasia, which is located within the extreme C-terminal domain (CTD) of p53, an unstructured, flexible region (residues 367-393) of major importance for the regulation of the protein. Based on the three-dimensional structure of a carboxyl-terminal peptide of p53 in complex with the S100B protein, which is involved in regulation of the tumor suppressor activity, a model of wild type (WT) and mutant extreme CTD was developed by molecular modeling and molecular dynamics simulation. It was found that the G389E amino acid replacement has negligible effects on free p53 in solution whereas it significantly affects the interactions of p53 with the S100B protein. The results suggest that the observed mutation may interfere with p53 transcription activation and provide useful information for site-directed mutagenesis experiments.

Mechanical influences in bacterial morphogenesis and cell division

NASA Astrophysics Data System (ADS)

Sun, Sean

2010-03-01

Bacterial cells utilize a ring-like organelle (the Z-ring) to accomplish cell division. The Z-ring actively generates a contractile force and influences cell wall growth. We will discuss a general model of bacterial morphogenesis where mechanical forces are coupled to the growth dynamics of the cell wall. The model suggests a physical mechanism that determines the shapes of bacteria cells. The roles of several bacterial cytoskeletal proteins and the Z-ring are discussed. We will also explore molecular mechanisms of force generation by the Z-ring and how cells can generate mechanical forces without molecular motors.

Molecular Mechanisms of Inner Ear Development

PubMed Central

Wu, Doris K.; Kelley, Matthew W.

2012-01-01

The inner ear is a structurally complex vertebrate organ built to encode sound, motion, and orientation in space. Given its complexity, it is not surprising that inner ear dysfunction is a relatively common consequence of human genetic mutation. Studies in model organisms suggest that many genes currently known to be associated with human hearing impairment are active during embryogenesis. Hence, the study of inner ear development provides a rich context for understanding the functions of genes implicated in hearing loss. This chapter focuses on molecular mechanisms of inner ear development derived from studies of model organisms. PMID:22855724

Insight into the novel inhibition mechanism of apigenin to Pneumolysin by molecular modeling

NASA Astrophysics Data System (ADS)

Niu, Xiaodi; Yang, Yanan; Song, Meng; Wang, Guizhen; Sun, Lin; Gao, Yawen; Wang, Hongsu

2017-11-01

In this study, the mechanism of apigenin inhibition was explored using molecular modelling, binding energy calculation, and mutagenesis assays. Energy decomposition analysis indicated that apigenin binds in the gap between domains 3 and 4 of PLY. Using principal component analysis, we found that binding of apigenin to PLY weakens the motion of domains 3 and 4. Consequently, these domains cannot complete the transition from monomer to oligomer, thereby blocking oligomerisation of PLY and counteracting its haemolytic activity. This inhibitory mechanism was confirmed by haemolysis assays, and these findings will promote the future development of an antimicrobial agent.

Molecular modeling of methyl-α-Neu5Ac analogues docked against cholera toxin--a molecular dynamics study.

PubMed

Blessy, J Jino; Sharmila, D Jeya Sundara

2015-02-01

Molecular modeling of synthetic methyl-α-Neu5Ac analogues modified in C-9 position was investigated by molecular docking and molecular dynamics (MD) simulation methods. Methyl-α-Neu5Ac analogues were docked against cholera toxin (CT) B subunit protein and MD simulations were carried out for three Methyl-α-Neu5Ac analogue-CT complexes (30, 10 and 10 ns) to estimate the binding activity of cholera toxin-Methyl-α-Neu5Ac analogues using OPLS_2005 force field. In this study, direct and water mediated hydrogen bonds play a vital role that exist between the methyl-α-9-N-benzoyl-amino-9-deoxy-Neu5Ac (BENZ)-cholera toxin active site residues. The Energy plot, RMSD and RMSF explain that the simulation was stable throughout the simulation run. Transition of phi, psi and omega angle for the complex was calculated. Molecular docking studies could be able to identify the binding mode of methyl-α-Neu5Ac analogues in the binding site of cholera toxin B subunit protein. MD simulation for Methyl-α-9-N-benzoyl-amino-9-deoxy-Neu5Ac (BENZ), Methyl-α-9-N-acetyl-9-deoxy-9-amino-Neu5Ac and Methyl-α-9-N-biphenyl-4-acetyl-deoxy-amino-Neu5Ac complex with CT B subunit protein was carried out, which explains the stable nature of interaction. These methyl-α-Neu5Ac analogues that have computationally acceptable pharmacological properties may be used as novel candidates for drug design for cholera disease.

In-vitro anticoagulant activity of fucoidan derivatives from brown seaweed Laminaria japonica

NASA Astrophysics Data System (ADS)

Wang, Jing; Zhang, Quanbin; Zhang, Zhongshan; Hou, Yun; Zhang, Hong

2011-05-01

Fucoidan, a group of sulfated heteropolysaccharides, was extracted from Laminaria japonica, an important economic alga species in China. The anticoagulant activity of fucoidan and its derivatives (including sulfated, phosphorylated, and aminated fucoidan) was examined using in-vitro anticoagulant systems. The correlation between chemical variations within the fucoidan group and anticoagulant activity was determined. The in-vitro anticoagulant properties of fucoidan and its derivatives were determined by measuring activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT). The results indicate anticoagulant activity in all samples using APTT and TT assays; however, only the fucoidan derivatives affected the PT assay. Thus, the fucoidan derivatives were able to inhibit both intrinsic and extrinsic blood coagulants. Fucoidan (FPS) and its derivatives presented better anticoagulant activity than low molecular weight fucoidan (DFPS) and its derivatives, suggesting that molecular weight and proper conformation are contributing factors for anticoagulant activity of polysaccharides. Amino groups have a positive charge and can thus change the charge density of fucoidan. Accordingly, among the tested samples, aminated fucoidan (NF) was the most active reflecting the importance of charge density for anticoagulant activity. Available data obtained using in-vitro models suggest that the sulfate content, sulfate/total-sugar ratio, molecular weight, and the substituted group of fucoidan are important factors for anticoagulant activity but that the influence of sulfate, phosphate and amino groups on anticoagulant activity was different.

Docking, molecular dynamics and quantitative structure-activity relationship studies for HEPTs and DABOs as HIV-1 reverse transcriptase inhibitors.

PubMed

Mao, Yating; Li, Yan; Hao, Ming; Zhang, Shuwei; Ai, Chunzhi

2012-05-01

As a key component in combination therapy for acquired immunodeficiency syndrome (AIDS), non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been proven to be an essential way in stopping HIV-1 replication. In the present work, in silico studies were conducted on a series of 119 NNRTIs, including 1-(2-hydroxyethoxymethyl)-6-(phenylthio)thymine (HEPT) and dihydroalkoxybenzyloxopyrimidine (DABO) derivatives by using the comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), docking simulations and molecular dynamics (MD). The statistical results of the optimal model, the ligand-based CoMSIA one (Q(2) = 0.48, R(ncv)(2) =0.847, R(pre)(2) = 0.745) validates its satisfactory predictive capacity both internally and externally. The contour maps, docking and MD results correlate well with each other, drawing conclusions as follows: 1) Compounds with bulky substituents in position-6 of ring A, hydrophobic groups around position- 1, 2, 6 are preferable to the biological activities; 2) Two hydrogen bonds between RT inhibitor and the Tyr 318, Lys 101 residues, respectively, and a π-π bond between the inhibitor and Trp 188 are formed and crucial to the orientation of the active conformation of the molecules; 3) The binding pocket is essentially hydrophobic, which are determined by residues such as Trp 229, Tyr 318, Val 179, Tyr 188 and Val 108, and hydrophobic substituents may bring an improvement to the biological activity; 4) DABO and HEPT derivatives have different structures but take a similar mechanism to inhibit RT. The potency difference between two isomers in HEPTs can be explained by the distinct locations of the 6-naphthylmethyl substituent and the reasons are explained in details. All these results could be employed to alter the structural scaffold in order to develop new HIV-1 RT inhibitors that have an improved biological property. To the best of our knowledge, this is the first report on 3D-QSAR modeling of this series of HEPT and DABO NNRTs. The QSAR model and the information derived, we hope, will be of great help in presenting clear guidelines and accurate activity predictions for newly designed HIV-1 reverse transcriptase (RT) inhibitor.

A molecular model for the active site of S-adenosyl- l-homocysteine hydrolase

NASA Astrophysics Data System (ADS)

Yeh, Jerry C.; Borchardt, Ronald T.; Vedani, Angelo

1991-06-01

S-adenosyl- l-homocysteine hydrolase (AdoHcy hydrolase, EC 3.3.1.1.), a specific target for antiviral drug design, catalyzes the hydrolysis of AdoHcy to adenosine (Ado) and homocysteine (Hcy) as well as the synthesis of AdoHcy from Ado and Hcy. The enzyme isolated from different sources has been shown to contain tightly bound NAD+. Based on the 2.0 Å-resolution X-ray crystal structure of dogfish lactate dehydrogenase (LDH), which is functionally homologous to AdoHcy hydrolase, and the primary sequence of rat liver AdoHcy hydrolase, we have derived a molecular model of an extended active site for AdoHcy hydrolase. The computational mutation was performed using the software MUTAR (Yeh et al., University of Kansas, Lawrence), followed by molecular mechanics optimizations using the programs AMBER (Singh et al., University of California, San Francisco) and YETI (Vedani, University of Kansas). Solvation of the model structure was achieved by use of the program SOLVGEN (Jacober, University of Kansas); 56 water molecules were explicitly included in all refinements. Some of these may be involved in the catalytic reaction. We also studied a model of the complex of AdoHcy hydrolase with NAD+, as well as the ternary complexes of the redox reaction catalyzed by AdoHcy hydrolase and has been used to differentiate the relative binding strength of inhibitors.

Exploring possible mechanisms of action for the nanotoxicity and protein binding of decorated nanotubes: interpretation of physicochemical properties from optimal QSAR models.

PubMed

Esposito, Emilio Xavier; Hopfinger, Anton J; Shao, Chi-Yu; Su, Bo-Han; Chen, Sing-Zuo; Tseng, Yufeng Jane

2015-10-01

Carbon nanotubes have become widely used in a variety of applications including biosensors and drug carriers. Therefore, the issue of carbon nanotube toxicity is increasingly an area of focus and concern. While previous studies have focused on the gross mechanisms of action relating to nanomaterials interacting with biological entities, this study proposes detailed mechanisms of action, relating to nanotoxicity, for a series of decorated (functionalized) carbon nanotube complexes based on previously reported QSAR models. Possible mechanisms of nanotoxicity for six endpoints (bovine serum albumin, carbonic anhydrase, chymotrypsin, hemoglobin along with cell viability and nitrogen oxide production) have been extracted from the corresponding optimized QSAR models. The molecular features relevant to each of the endpoint respective mechanism of action for the decorated nanotubes are also discussed. Based on the molecular information contained within the optimal QSAR models for each nanotoxicity endpoint, either the decorator attached to the nanotube is directly responsible for the expression of a particular activity, irrespective of the decorator's 3D-geometry and independent of the nanotube, or those decorators having structures that place the functional groups of the decorators as far as possible from the nanotube surface most strongly influence the biological activity. These molecular descriptors are further used to hypothesize specific interactions involved in the expression of each of the six biological endpoints. Copyright © 2015 Elsevier Inc. All rights reserved.

Molecular targets of celastrol derived from Thunder of God Vine: potential role in the treatment of inflammatory disorders and cancer.

PubMed

Kannaiyan, Radhamani; Shanmugam, Muthu K; Sethi, Gautam

2011-04-01

Identification of active constituents and their molecular targets from traditional medicine is an enormous opportunity for modern pharmacology. Celastrol is one such compound that was originally identified from traditional Chinese medicine (Thunder of God Vine) almost three decades ago and generally used for the treatment of inflammatory and auto-immune diseases. Celastrol has attracted great interest recently, especially for its potential anti-inflammatory and anti-cancer activities. The anti-inflammatory effects of this triterpene have been demonstrated in animal models of different inflammatory diseases, including arthritis, Alzheimer's disease, asthma, and systemic lupus erythematosus. This triterpene has also been found to inhibit the proliferation of a variety of tumor cells and suppress tumor initiation, promotion and metastasis in various cancer models in vivo. Celastrol's ability to modulate the expression of pro-inflammatory cytokines, MHC II, HO-1, iNOS, NF-κB, Notch-1, AKT/mTOR, CXCR4, TRAIL receptors DR4 and DR5, CHOP, JNK, VEGF, adhesion molecules, proteasome activity, topoisomerase II, potassium channels, and heat shock response has been reported. This review describes the various molecular targets of celastrol, cellular responses to celastrol, and animal studies with celastrol in cancer and other inflammatory disorders. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Synthesis, biological evaluation and molecular modeling studies of imidazo[1,2-a]pyridines derivatives as protein kinase inhibitors.

PubMed

Lawson, Marie; Rodrigo, Jordi; Baratte, Blandine; Robert, Thomas; Delehouzé, Claire; Lozach, Olivier; Ruchaud, Sandrine; Bach, Stéphane; Brion, Jean-Daniel; Alami, Mouad; Hamze, Abdallah

2016-11-10

We report here the synthesis, the biological evaluation and the molecular modeling studies of new imidazo[1,2-a]pyridines derivatives designed as potent kinase inhibitors. This collection was obtained from 2-aminopyridines and 2-bromoacetophenone which afforded final compound in only one step. The bioactivity of this family of new compounds was tested using protein kinase and ATP competition assays. The structure-activity relationship (SAR) revealed that six compounds inhibit DYRK1A and CLK1 at a micromolar range. Docking studies provided possible explanations that correlate with the SAR data. The most active compound 4c inhibits CLK1 (IC50 of 0.7 μM) and DYRK1A (IC50 of 2.6 μM). Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Acquired resistance mechanisms to tyrosine kinase inhibitors in lung cancer with activating epidermal growth factor receptor mutation--diversity, ductility, and destiny.

PubMed

Suda, Kenichi; Mizuuchi, Hiroshi; Maehara, Yoshihiko; Mitsudomi, Tetsuya

2012-12-01

Lung cancers that harbor somatic activating mutations in the gene for the epidermal growth factor receptor (EGFR) depend on mutant EGFR for their proliferation and survival; therefore, lung cancer patients with EGFR mutations often dramatically respond to orally available EGFR tyrosine kinase inhibitors (TKIs). However, emergence of acquired resistance is virtually inevitable, thus limiting improvement in patient outcomes. To elucidate and overcome this acquired resistance, multidisciplinary basic and clinical investigational approaches have been applied, using in vitro cell line models or samples obtained from lung cancer patients treated with EGFR-TKIs. These efforts have revealed several acquired resistance mechanisms and candidates, including EGFR secondary mutations (T790M and other rare mutations), MET amplification, PTEN downregulation, CRKL amplification, high-level HGF expression, FAS-NFκB pathway activation, epithelial-mesenchymal transition, and conversion to small cell lung cancer. Interestingly, cancer cells harbor potential destiny and ductility together in acquiring resistance to EGFR-TKIs, as shown in in vitro acquired resistance models. Molecular mechanisms of "reversible EGFR-TKI tolerance" that occur in early phase EGFR-TKI exposure have been identified in cell line models. Furthermore, others have reported molecular markers that can predict response to EGFR-TKIs in clinical settings. Deeper understanding of acquired resistance mechanisms to EGFR-TKIs, followed by the development of molecular target drugs that can overcome the resistance, might turn this fatal disease into a chronic disorder.

Molecular modeling of the AhR structure and interactions can shed light on ligand-dependent activation and transformation mechanisms.

PubMed

Bonati, Laura; Corrada, Dario; Tagliabue, Sara Giani; Motta, Stefano

2017-02-01

Molecular modeling has given important contributions to elucidation of the main stages in the AhR signal transduction pathway. Despite the lack of experimentally determined structures of the AhR functional domains, information derived from homologous systems has been exploited for modeling their structure and interactions. Homology models of the AhR PASB domain have provided information on the binding cavity and contributed to elucidate species-specific differences in ligand binding. Molecular Docking simulations of the ligand binding process have given insights into differences in binding of diverse agonists, antagonists, and selective AhR modulators, and their application to virtual screening of large databases of compounds have allowed identification of novel AhR ligands. Recently available structural information on protein-protein and protein-DNA complexes of other bHLH-PAS systems has opened the way for modeling the AhR:ARNT dimer structure and investigating the mechanisms of AhR transformation and DNA binding. Future research directions should include simulation of the protein dynamics to obtain a more reliable description of intermolecular interactions involved in signal transmission.

Self-consistent Non-LTE Model of Infrared Molecular Emissions and Oxygen Dayglows in the Mesosphere and Lower Thermosphere

NASA Technical Reports Server (NTRS)

Feofilov, Artem G.; Yankovsky, Valentine A.; Pesnell, William D.; Kutepov, Alexander A.; Goldberg, Richard A.; Mauilova, Rada O.

2007-01-01

We present the new version of the ALI-ARMS (for Accelerated Lambda Iterations for Atmospheric Radiation and Molecular Spectra) model. The model allows simultaneous self-consistent calculating the non-LTE populations of the electronic-vibrational levels of the O3 and O2 photolysis products and vibrational level populations of CO2, N2,O2, O3, H2O, CO and other molecules with detailed accounting for the variety of the electronic-vibrational, vibrational-vibrational and vibrational-translational energy exchange processes. The model was used as the reference one for modeling the O2 dayglows and infrared molecular emissions for self-consistent diagnostics of the multi-channel space observations of MLT in the SABER experiment It also allows reevaluating the thermalization efficiency of the absorbed solar ultraviolet energy and infrared radiative cooling/heating of MLT by detailed accounting of the electronic-vibrational relaxation of excited photolysis products via the complex chain of collisional energy conversion processes down to the vibrational energy of optically active trace gas molecules.

Consequences of Molecular-Scale Non-Equilibrium Activity on the Dynamics and Mechanics of Self-Assembled Actin-Based Structures and Materials

NASA Astrophysics Data System (ADS)

Marshall Mccall, Patrick

Living cells are hierarchically self-organized forms of active soft matter: molecules on the nanometer scale form functional structures and organelles on the micron scale, which then compose cells on the scale of 10s of microns. While the biological functions of intracellular organelles are defined by the composition and properties of the structures themselves, how those bulk properties emerge from the properties and interactions of individual molecules remains poorly understood. Actin, a globular protein which self-assembles into dynamic semi-flexible polymers, is the basic structural material of cells and the major component of many functional organelles. In this thesis, I have used purified actin as a model system to explore the interplay between molecular-scale dynamics and organelle-scale functionality, with particular focus on the role of molecular-scale non-equilibrium activity. One of the most canonical forms of molecular-scale non-equilibrium activity is that of mechanoenzymes, also called motor proteins. These proteins utilized the free energy liberated by hydrolysis of ATP to perform mechanical work, thereby introducing non-equilibrium "active" stresses on the molecular scale. Combining experiments with mathematical modeling, we demonstrate in this thesis that non-equilibrium motor activity is sufficient to drive self-organization and pattern formation of the multimeric actin-binding motor protein Myosin II on 1D reconstituted actomyosin bundles. Like myosin, actin is itself an ATPase. However, nono-equilibrium ATP hydrolysis on actin is known to regulate the stability and assembly kinetics of actin filaments rather than generate active stresses per se. At the level of single actin filaments, the inhomogeneous nucleotide composition generated along the filament length by hydrolysis directs binding of regulatory proteins like cofilin, which mediate filament disassembly and thereby accelerate actin filament turnover. The concequences of this non-equilibrium turnover on the steady-state properties of collections of filaments remained unclear. Here, I reconstituted tunable, non-equilibrium actin turnover dynamics in entangled solutions of actin filaments as a model of the actin cortex of living cells. We found that this non-equilibrium turnover decouples solution mechanics from microstructure, enabling structurally indistinguishable materials to behave effectively as either viscous fluids or elastic gels. Additionally, we employed computer simulations to identify the dynamical regime in which actin turnover controls the effective viscosity of 2D cross-linked actin networks in the presence of motors. Additionally, I examine in this thesis the localization and self-assembly of actin filaments in condensed liquid phases called polyelectrolyte coacervates as a model membrane-less organelle. We find that concentration of actin through spontaneous partitioning preferentially to the coacervate phase accelerates the assembly of filaments. These filaments then localize to the coacervate-bulk interface, generating particles with visco-elastic shells surrounding liquid cores. In this case, the properties of the condensed phase enable regulation of actin assembly dynamics.

Molecular Dynamics Simulations Reveal the Mechanisms of Allosteric Activation of Hsp90 by Designed Ligands

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.

Analysis of conjugation of chloramphenicol and hemoglobin by fluorescence, circular dichroism and molecular modeling

NASA Astrophysics Data System (ADS)

Ding, Fei; Liu, Wei; Sun, Ye; Yang, Xin-Ling; Sun, Ying; Zhang, Li

2012-01-01

Chloramphenicol is a low cost, broad spectrum, highly active antibiotic, and widely used in the treatment of serious infections, including typhoid fever and other life-threatening infections of the central nervous system and respiratory tract. The purpose of the present study was to examine the conjugation of chloramphenicol with hemoglobin (Hb) and compared with albumin at molecular level, utilizing fluorescence, UV/vis absorption, circular dichroism (CD) as well as molecular modeling. Fluorescence data indicate that drug bind Hb generate quenching via static mechanism, this corroborates UV/vis absorption measurements that the ground state complex formation with an affinity of 10 4 M -1, and the driving forces in the Hb-drug complex are hydrophilic interactions and hydrogen bonds, as derived from computational model. The accurate binding site of drug has been identified from the analysis of fluorescence and molecular modeling, α1β2 interface of Hb was assigned to possess high-affinity for drug, which located at the β-37 Trp nearby. The structural investigation of the complexed Hb by synchronous fluorescence, UV/vis absorption, and CD observations revealed some degree of Hb structure unfolding upon complexation. Based on molecular modeling, we can draw the conclusion that the binding affinity of drug with albumin is superior, compared with Hb. These phenomena can provide salient information on the absorption, distribution, pharmacology, and toxicity of chloramphenicol and other drugs which have analogous configuration with chloramphenicol.

Multitargeted therapy of cancer by silymarin

PubMed Central

Ramasamy, Kumaraguruparan; Agarwal, Rajesh

2008-01-01

Silymarin, a flavonolignan from milk thistle (Silybum marianum) plant, is used for the protection against various liver conditions in both clinical settings and experimental models. In this review, we summarize the recent investigations and mechanistic studies regarding possible molecular targets of silymarin for cancer prevention. Number of studies has established the cancer chemopreventive role of silymarin in both in vivo and in vitro models. Silymarin modulates imbalance between cell survival and apoptosis through interference with the expressions of cell cycle regulators and proteins involved in apoptosis. In addition, silymarin also showed anti-inflammatory as well as anti-metastatic activity. Further, the protective effects of silymarin and its major active constituent, silibinin, studied in various tissues, suggest a clinical application in cancer patients as an adjunct to estabilished therapies, to prevent or reduce chemotherapy as well as radiotherapy-induced toxicity. This review focuses on the chemistry and analogues of silymarin, multiple possible molecular mechanisms, in vitro as well as in vivo anticancer activities, and studies on human clinical trials. PMID:18472213

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ghosh, Arun K.; Takayama, Jun; Rao, Kalapala Venkateswar

The design, synthesis, X-ray crystal structure, molecular modeling, and biological evaluation of a series of new generation SARS-CoV PLpro inhibitors are described. A new lead compound 3 (6577871) was identified via high-throughput screening of a diverse chemical library. Subsequently, we carried out lead optimization and structure-activity studies to provide a series of improved inhibitors that show potent PLpro inhibition and antiviral activity against SARS-CoV infected Vero E6 cells. Interestingly, the (S)-Me inhibitor 15h (enzyme IC{sub 50} = 0.56 {mu}M; antiviral EC{sub 50} = 9.1 {mu}M) and the corresponding (R)-Me 15g (IC{sub 50} = 0.32 {mu}M; antiviral EC{sub 50} = 9.1more » {mu}M) are the most potent compounds in this series, with nearly equivalent enzymatic inhibition and antiviral activity. A protein-ligand X-ray structure of 15g-bound SARS-CoV PLpro and a corresponding model of 15h docked to PLpro provide intriguing molecular insight into the ligand-binding site interactions.« less

A combined LS-SVM & MLR QSAR workflow for predicting the inhibition of CXCR3 receptor by quinazolinone analogs.

PubMed

Afantitis, Antreas; Melagraki, Georgia; Sarimveis, Haralambos; Koutentis, Panayiotis A; Igglessi-Markopoulou, Olga; Kollias, George

2010-05-01

A novel QSAR workflow is constructed that combines MLR with LS-SVM classification techniques for the identification of quinazolinone analogs as "active" or "non-active" CXCR3 antagonists. The accuracy of the LS-SVM classification technique for the training set and test was 100% and 90%, respectively. For the "active" analogs a validated MLR QSAR model estimates accurately their I-IP10 IC(50) inhibition values. The accuracy of the QSAR model (R (2) = 0.80) is illustrated using various evaluation techniques, such as leave-one-out procedure (R(LOO2)) = 0.67) and validation through an external test set (R(pred2) = 0.78). The key conclusion of this study is that the selected molecular descriptors, Highest Occupied Molecular Orbital energy (HOMO), Principal Moment of Inertia along X and Y axes PMIX and PMIZ, Polar Surface Area (PSA), Presence of triple bond (PTrplBnd), and Kier shape descriptor ((1) kappa), demonstrate discriminatory and pharmacophore abilities.

Active food packaging based on molecularly imprinted polymers: study of the release kinetics of ferulic acid.

PubMed

Otero-Pazos, Pablo; Rodríguez-Bernaldo de Quirós, Ana; Sendón, Raquel; Benito-Peña, Elena; González-Vallejo, Victoria; Moreno-Bondi, M Cruz; Angulo, Immaculada; Paseiro-Losada, Perfecto

2014-11-19

A novel active packaging based on molecularly imprinted polymer (MIP) was developed for the controlled release of ferulic acid. The release kinetics of ferulic acid from the active system to food simulants (10, 20, and 50% ethanol (v/v), 3% acetic acid (w/v), and vegetable oil), substitutes (95% ethanol (v/v) and isooctane), and real food samples at different temperatures were studied. The key parameters of the diffusion process were calculated by using a mathematical modeling based on Fick's second law. The ferulic acid release was affected by the temperature as well as the percentage of ethanol of the simulant. The fastest release occurred in 95% ethanol (v/v) at 20 °C. The diffusion coefficients (D) obtained ranged between 1.8 × 10(-11) and 4.2 × 10(-9) cm(2)/s. A very good correlation between experimental and estimated data was obtained, and consequently the model could be used to predict the release of ferulic acid into food simulants and real food samples.

Potential New H1N1 Neuraminidase Inhibitors from Ferulic Acid and Vanillin: Molecular Modelling, Synthesis and in Vitro Assay

NASA Astrophysics Data System (ADS)

Hariono, Maywan; Abdullah, Nurshariza; Damodaran, K. V.; Kamarulzaman, Ezatul E.; Mohamed, Nornisah; Hassan, Sharifah Syed; Shamsuddin, Shaharum; Wahab, Habibah A.

2016-12-01

We report the computational and experimental efforts in the design and synthesis of novel neuraminidase (NA) inhibitors from ferulic acid and vanillin. Two proposed ferulic acid analogues, MY7 and MY8 were predicted to inhibit H1N1 NA using molecular docking. From these two analogues, we designed, synthesised and evaluated the biological activities of a series of ferulic acid and vanillin derivatives. The enzymatic H1N1 NA inhibition assay showed MY21 (a vanillin derivative) has the lowest IC50 of 50 μM. In contrast, the virus inhibition assay showed MY15, a ferulic acid derivative has the best activity with the EC50 of ~0.95 μM. Modelling studies further suggest that these predicted activities might be due to the interactions with conserved and essential residues of NA with ΔGbind values comparable to those of oseltamivir and zanamivir, the two commercial NA inhibitors.

Augmented multivariate image analysis applied to quantitative structure-activity relationship modeling of the phytotoxicities of benzoxazinone herbicides and related compounds on problematic weeds.

PubMed

Freitas, Mirlaine R; Matias, Stella V B G; Macedo, Renato L G; Freitas, Matheus P; Venturin, Nelson

2013-09-11

Two of major weeds affecting cereal crops worldwide are Avena fatua L. (wild oat) and Lolium rigidum Gaud. (rigid ryegrass). Thus, development of new herbicides against these weeds is required; in line with this, benzoxazinones, their degradation products, and analogues have been shown to be important allelochemicals and natural herbicides. Despite earlier structure-activity studies demonstrating that hydrophobicity (log P) of aminophenoxazines correlates to phytotoxicity, our findings for a series of benzoxazinone derivatives do not show any relationship between phytotoxicity and log P nor with other two usual molecular descriptors. On the other hand, a quantitative structure-activity relationship (QSAR) analysis based on molecular graphs representing structural shape, atomic sizes, and colors to encode other atomic properties performed very accurately for the prediction of phytotoxicities of these compounds against wild oat and rigid ryegrass. Therefore, these QSAR models can be used to estimate the phytotoxicity of new congeners of benzoxazinone herbicides toward A. fatua L. and L. rigidum Gaud.

Modeling Shear Induced Von Willebrand Factor Binding to Collagen

NASA Astrophysics Data System (ADS)

Dong, Chuqiao; Wei, Wei; Morabito, Michael; Webb, Edmund; Oztekin, Alparslan; Zhang, Xiaohui; Cheng, Xuanhong

2017-11-01

Von Willebrand factor (vWF) is a blood glycoprotein that binds with platelets and collagen on injured vessel surfaces to form clots. VWF bioactivity is shear flow induced: at low shear, binding between VWF and other biological entities is suppressed; for high shear rate conditions - as are found near arterial injury sites - VWF elongates, activating its binding with platelets and collagen. Based on parameters derived from single molecule force spectroscopy experiments, we developed a coarse-grain molecular model to simulate bond formation probability as a function of shear rate. By introducing a binding criterion that depends on the conformation of a sub-monomer molecular feature of our model, the model predicts shear-induced binding, even for conditions where binding is highly energetically favorable. We further investigate the influence of various model parameters on the ability to predict shear-induced binding (vWF length, collagen site density and distribution, binding energy landscape, and slip/catch bond length) and demonstrate parameter ranges where the model provides good agreement with existing experimental data. Our results may be important for understanding vWF activity and also for achieving targeted drug therapy via biomimetic synthetic molecules. National Science Foundation (NSF),Division of Mathematical Sciences (DMS).

Noscapinoids with anti-cancer activity against human acute lymphoblastic leukemia cells (CEM): a three dimensional chemical space pharmacophore modeling and electronic feature analysis.

PubMed

Naik, Pradeep K; Santoshi, Seneha; Joshi, Harish C

2012-01-01

We have identified a new class of microtubule-binding compounds-noscapinoids-that alter microtubule dynamics at stoichiometric concentrations without affecting tubulin polymer mass. Noscapinoids show great promise as chemotherapeutic agents for the treatment of human cancers. To investigate the structural determinants of noscapinoids responsible for anti-cancer activity, we tested 36 structurally diverse noscapinoids in human acute lymphoblastic leukemia cells (CEM). The IC(50) values of these noscapinoids vary from 1.2 to 56.0 μM. Pharmacophore models of anti-cancer activity were generated that identify two hydrogen bond acceptors, two aromatic rings, two hydrophobic groups, and one positively charged group as essential structural features. Additionally, an atom-based quantitative structure-activity relationship (QSAR) model was developed that gave a statistically satisfying result (R(2) = 0.912, Q(2) = 0.908, Pearson R = 0.951) and effectively predicts the anti-cancer activity of training and test set compounds. The pharmacophore model presented here is well supported by electronic property analysis using density functional theory at B3LYP/3-21*G level. Molecular electrostatic potential, particularly localization of negative potential near oxygen atoms of the dimethoxy isobenzofuranone ring of active compounds, matched the hydrogen bond acceptor feature of the generated pharmacophore. Our results further reveal that all active compounds have smaller lowest unoccupied molecular orbital (LUMO) energies concentrated over the dimethoxy isobenzofuranone ring, azido group, and nitro group, which is indicative of the electron acceptor capacity of the compounds. Results obtained from this study will be useful in the efficient design and development of more active noscapinoids.

Understanding the determinants of selectivity in drug metabolism through modeling of dextromethorphan oxidation by cytochrome P450

PubMed Central

Oláh, Julianna; Mulholland, Adrian J.; Harvey, Jeremy N.

2011-01-01

Cytochrome P450 enzymes play key roles in the metabolism of the majority of drugs. Improved models for prediction of likely metabolites will contribute to drug development. In this work, two possible metabolic routes (aromatic carbon oxidation and O-demethylation) of dextromethorphan are compared using molecular dynamics (MD) simulations and density functional theory (DFT). The DFT results on a small active site model suggest that both reactions might occur competitively. Docking and MD studies of dextromethorphan in the active site of P450 2D6 show that the dextromethorphan is located close to heme oxygen in a geometry apparently consistent with competitive metabolism. In contrast, calculations of the reaction path in a large protein model [using a hybrid quantum mechanical–molecular mechanics (QM/MM) method] show a very strong preference for O-demethylation, in accordance with experimental results. The aromatic carbon oxidation reaction is predicted to have a high activation energy, due to the active site preventing formation of a favorable transition-state structure. Hence, the QM/MM calculations demonstrate a crucial role of many active site residues in determining reactivity of dextromethorphan in P450 2D6. Beyond substrate binding orientation and reactivity of Compound I, successful metabolite predictions must take into account the detailed mechanism of oxidation in the protein. These results demonstrate the potential of QM/MM methods to investigate specificity in drug metabolism. PMID:21444768

Thermodynamic Modeling of Organic-Inorganic Aerosols with the Group-Contribution Model AIOMFAC

NASA Astrophysics Data System (ADS)

Zuend, A.; Marcolli, C.; Luo, B. P.; Peter, T.

2009-04-01

Liquid aerosol particles are - from a physicochemical viewpoint - mixtures of inorganic salts, acids, water and a large variety of organic compounds (Rogge et al., 1993; Zhang et al., 2007). Molecular interactions between these aerosol components lead to deviations from ideal thermodynamic behavior. Strong non-ideality between organics and dissolved ions may influence the aerosol phases at equilibrium by means of liquid-liquid phase separations into a mainly polar (aqueous) and a less polar (organic) phase. A number of activity models exists to successfully describe the thermodynamic equilibrium of aqueous electrolyte solutions. However, the large number of different, often multi-functional, organic compounds in mixed organic-inorganic particles is a challenging problem for the development of thermodynamic models. The group-contribution concept as introduced in the UNIFAC model by Fredenslund et al. (1975), is a practical method to handle this difficulty and to add a certain predictability for unknown organic substances. We present the group-contribution model AIOMFAC (Aerosol Inorganic-Organic Mixtures Functional groups Activity Coefficients), which explicitly accounts for molecular interactions between solution constituents, both organic and inorganic, to calculate activities, chemical potentials and the total Gibbs energy of mixed systems (Zuend et al., 2008). This model enables the computation of vapor-liquid (VLE), liquid-liquid (LLE) and solid-liquid (SLE) equilibria within one framework. Focusing on atmospheric applications we considered eight different cations, five anions and a wide range of alcohols/polyols as organic compounds. With AIOMFAC, the activities of the components within an aqueous electrolyte solution are very well represented up to high ionic strength. We show that the semi-empirical middle-range parametrization of direct organic-inorganic interactions in alcohol-water-salt solutions enables accurate computations of vapor-liquid and liquid-liquid equilibria. References Fredenslund, A., Jones, R. L., and Prausnitz, J. M.: Group-Contribution Estimation of Activity Coefficients in Nonideal Liquid Mixtures, AIChE J., 21, 1086-1099, 1975. Rogge, W. F., Mazurek, M. A., Hildemann, L. M., Cass, G. R., and Simoneit, B. R. T.: Quantification of Urban Organic Aerosols at a Molecular Level: Identification, Abundance and Seasonal Variation, Atmos. Environ., 27, 1309-1330, 1993. Zhang, Q. et al.: Ubiquity and dominance of oxygenated species in organic aerosols in anthropogenically influenced Northern Hemisphere midlatitudes, Geophys. Res. Lett., 34, L13 801, 2007. Zuend, A., Marcolli, C., Luo, B. P., and Peter, T.: A thermodynamic model of mixed organic-inorganic aerosols to predict activity coefficients, Atmos. Chem. Phys., 8, 4559-4593, 2008.

Wind from the black-hole accretion disk driving a molecular outflow in an active galaxy.

PubMed

Tombesi, F; Meléndez, M; Veilleux, S; Reeves, J N; González-Alfonso, E; Reynolds, C S

2015-03-26

Powerful winds driven by active galactic nuclei are often thought to affect the evolution of both supermassive black holes and their host galaxies, quenching star formation and explaining the close relationship between black holes and galaxies. Recent observations of large-scale molecular outflows in ultraluminous infrared galaxies support this quasar-feedback idea, because they directly trace the gas from which stars form. Theoretical models suggest that these outflows originate as energy-conserving flows driven by fast accretion-disk winds. Proposed connections between large-scale molecular outflows and accretion-disk activity in ultraluminous galaxies were incomplete because no accretion-disk wind had been detected. Conversely, studies of powerful accretion-disk winds have until now focused only on X-ray observations of local Seyfert galaxies and a few higher-redshift quasars. Here we report observations of a powerful accretion-disk wind with a mildly relativistic velocity (a quarter that of light) in the X-ray spectrum of IRAS F11119+3257, a nearby (redshift 0.189) optically classified type 1 ultraluminous infrared galaxy hosting a powerful molecular outflow. The active galactic nucleus is responsible for about 80 per cent of the emission, with a quasar-like luminosity of 1.5 × 10(46) ergs per second. The energetics of these two types of wide-angle outflows is consistent with the energy-conserving mechanism that is the basis of the quasar feedback in active galactic nuclei that lack powerful radio jets (such jets are an alternative way to drive molecular outflows).

Students' use of atomic and molecular models in learning chemistry

NASA Astrophysics Data System (ADS)

O'Connor, Eileen Ann

1997-09-01

The objective of this study was to investigate the development of introductory college chemistry students' use of atomic and molecular models to explain physical and chemical phenomena. The study was conducted during the first semester of the course at a University and College II. Public institution (Carnegie Commission of Higher Education, 1973). Students' use of models was observed during one-on-one interviews conducted over the course of the semester. The approach to introductory chemistry emphasized models. Students were exposed to over two-hundred and fifty atomic and molecular models during lectures, were assigned text readings that used over a thousand models, and worked interactively with dozens of models on the computer. These models illustrated various features of the spatial organization of valence electrons and nuclei in atoms and molecules. Despite extensive exposure to models in lectures, in textbook, and in computer-based activities, the students in the study based their explanation in large part on a simple Bohr model (electrons arranged in concentric circles around the nuclei)--a model that had not been introduced in the course. Students used visual information from their models to construct their explanation, while overlooking inter-atomic and intra-molecular forces which are not represented explicitly in the models. In addition, students often explained phenomena by adding separate information about the topic without either integrating or logically relating this information into a cohesive explanation. The results of the study demonstrate that despite the extensive use of models in chemistry instruction, students do not necessarily apply them appropriately in explaining chemical and physical phenomena. The results of this study suggest that for the power of models as aids to learning to be more fully realized, chemistry professors must give more attention to the selection, use, integration, and limitations of models in their instruction.

Application of computer-assisted molecular modeling for immunoassay of low molecular weight food contaminants: A review.

PubMed

Xu, Zhen-Lin; Shen, Yu-Dong; Beier, Ross C; Yang, Jin-Yi; Lei, Hong-Tao; Wang, Hong; Sun, Yuan-Ming

2009-08-11

Immunoassay for low molecular weight food contaminants, such as pesticides, veterinary drugs, and mycotoxins is now a well-established technique which meets the demand for a rapid, reliable, and cost-effective analytical method. However, due to limited understanding of the molecular structure of antibody binding sites and antigenic epitopes, as well as the intermolecular binding forces that come into play, the traditional 'trial and error' method used to develop antibodies still remains the method of choice. Therefore, development of enhanced immunochemical techniques for specific- and generic-assays, requires new approaches for antibody design that will improve affinity and specificity of the antibody in a more rapid and economic manner. Computer-assisted molecular modeling (CAMM) has been demonstrated to be a useful tool to help the immunochemist develop immunoassays. CAMM methods can be used to help direct improvements to important antibody features, and can provide insights into the effects of molecular structure on biological activity that are difficult or impossible to obtain in any other way. In this review, we briefly summarize applications of CAMM in immunoassay development, including assisting in hapten design, explaining cross-reactivity, modeling antibody-antigen interactions, and providing insights into the effects of the mouse body temperature on the three-dimensional conformation of a hapten during antibody production. The fundamentals and theory, programs and software, limitations, and prospects of CAMM in immunoassay development were also discussed.

Exploring Molecular Mechanisms of Paradoxical Activation in the BRAF Kinase Dimers: Atomistic Simulations of Conformational Dynamics and Modeling of Allosteric Communication Networks and Signaling Pathways

PubMed Central

Tse, Amanda; Verkhivker, Gennady M.

2016-01-01

The recent studies have revealed that most BRAF inhibitors can paradoxically induce kinase activation by promoting dimerization and enzyme transactivation. Despite rapidly growing number of structural and functional studies about the BRAF dimer complexes, the molecular basis of paradoxical activation phenomenon is poorly understood and remains largely hypothetical. In this work, we have explored the relationships between inhibitor binding, protein dynamics and allosteric signaling in the BRAF dimers using a network-centric approach. Using this theoretical framework, we have combined molecular dynamics simulations with coevolutionary analysis and modeling of the residue interaction networks to determine molecular determinants of paradoxical activation. We have investigated functional effects produced by paradox inducer inhibitors PLX4720, Dabrafenib, Vemurafenib and a paradox breaker inhibitor PLX7904. Functional dynamics and binding free energy analyses of the BRAF dimer complexes have suggested that negative cooperativity effect and dimer-promoting potential of the inhibitors could be important drivers of paradoxical activation. We have introduced a protein structure network model in which coevolutionary residue dependencies and dynamic maps of residue correlations are integrated in the construction and analysis of the residue interaction networks. The results have shown that coevolutionary residues in the BRAF structures could assemble into independent structural modules and form a global interaction network that may promote dimerization. We have also found that BRAF inhibitors could modulate centrality and communication propensities of global mediating centers in the residue interaction networks. By simulating allosteric communication pathways in the BRAF structures, we have determined that paradox inducer and breaker inhibitors may activate specific signaling routes that correlate with the extent of paradoxical activation. While paradox inducer inhibitors may facilitate a rapid and efficient communication via an optimal single pathway, the paradox breaker may induce a broader ensemble of suboptimal and less efficient communication routes. The central finding of our study is that paradox breaker PLX7904 could mimic structural, dynamic and network features of the inactive BRAF-WT monomer that may be required for evading paradoxical activation. The results of this study rationalize the existing structure-functional experiments by offering a network-centric rationale of the paradoxical activation phenomenon. We argue that BRAF inhibitors that amplify dynamic features of the inactive BRAF-WT monomer and intervene with the allosteric interaction networks may serve as effective paradox breakers in cellular environment. PMID:27861609

Phosphorylation and mutations of Ser(16) in human phenylalanine hydroxylase. Kinetic and structural effects.

PubMed

Miranda, Frederico Faria; Teigen, Knut; Thórólfsson, Matthías; Svebak, Randi M; Knappskog, Per M; Flatmark, Torgeir; Martínez, Aurora

2002-10-25

Phosphorylation of phenylalanine hydroxylase (PAH) at Ser(16) by cyclic AMP-dependent protein kinase is a post-translational modification that increases its basal activity and facilitates its activation by the substrate l-Phe. So far there is no structural information on the flexible N-terminal tail (residues 1-18), including the phosphorylation site. To get further insight into the molecular basis for the effects of phosphorylation on the catalytic efficiency and enzyme stability, molecular modeling was performed using the crystal structure of the recombinant rat enzyme. The most probable conformation and orientation of the N-terminal tail thus obtained indicates that phosphorylation of Ser(16) induces a local conformational change as a result of an electrostatic interaction between the phosphate group and Arg(13) as well as a repulsion by Glu(280) in the loop at the entrance of the active site crevice structure. The modeled reorientation of the N-terminal tail residues (Met(1)-Leu(15)) on phosphorylation is in agreement with the observed conformational change and increased accessibility of the substrate to the active site, as indicated by circular dichroism spectroscopy and the enzyme kinetic data for the full-length phosphorylated and nonphosphorylated human PAH. To further validate the model we have prepared and characterized mutants substituting Ser(16) with a negatively charged residue and found that S16E largely mimics the effects of phosphorylation of human PAH. Both the phosphorylated enzyme and the mutants with acidic side chains instead of Ser(16) revealed an increased resistance toward limited tryptic proteolysis and, as indicated by circular dichroism spectroscopy, an increased content of alpha-helical structure. In agreement with the modeled structure, the formation of an Arg(13) to Ser(16) phosphate salt bridge and the conformational change of the N-terminal tail also explain the higher stability toward limited tryptic proteolysis of the phosphorylated enzyme. The results obtained with the mutant R13A and E381A further support the model proposed for the molecular mechanism for the activation of the enzyme by phosphorylation.

DemQSAR: predicting human volume of distribution and clearance of drugs

NASA Astrophysics Data System (ADS)

Demir-Kavuk, Ozgur; Bentzien, Jörg; Muegge, Ingo; Knapp, Ernst-Walter

2011-12-01

In silico methods characterizing molecular compounds with respect to pharmacologically relevant properties can accelerate the identification of new drugs and reduce their development costs. Quantitative structure-activity/-property relationship (QSAR/QSPR) correlate structure and physico-chemical properties of molecular compounds with a specific functional activity/property under study. Typically a large number of molecular features are generated for the compounds. In many cases the number of generated features exceeds the number of molecular compounds with known property values that are available for learning. Machine learning methods tend to overfit the training data in such situations, i.e. the method adjusts to very specific features of the training data, which are not characteristic for the considered property. This problem can be alleviated by diminishing the influence of unimportant, redundant or even misleading features. A better strategy is to eliminate such features completely. Ideally, a molecular property can be described by a small number of features that are chemically interpretable. The purpose of the present contribution is to provide a predictive modeling approach, which combines feature generation, feature selection, model building and control of overtraining into a single application called DemQSAR. DemQSAR is used to predict human volume of distribution (VDss) and human clearance (CL). To control overtraining, quadratic and linear regularization terms were employed. A recursive feature selection approach is used to reduce the number of descriptors. The prediction performance is as good as the best predictions reported in the recent literature. The example presented here demonstrates that DemQSAR can generate a model that uses very few features while maintaining high predictive power. A standalone DemQSAR Java application for model building of any user defined property as well as a web interface for the prediction of human VDss and CL is available on the webpage of DemPRED: http://agknapp.chemie.fu-berlin.de/dempred/.

DemQSAR: predicting human volume of distribution and clearance of drugs.

PubMed

Demir-Kavuk, Ozgur; Bentzien, Jörg; Muegge, Ingo; Knapp, Ernst-Walter

2011-12-01

In silico methods characterizing molecular compounds with respect to pharmacologically relevant properties can accelerate the identification of new drugs and reduce their development costs. Quantitative structure-activity/-property relationship (QSAR/QSPR) correlate structure and physico-chemical properties of molecular compounds with a specific functional activity/property under study. Typically a large number of molecular features are generated for the compounds. In many cases the number of generated features exceeds the number of molecular compounds with known property values that are available for learning. Machine learning methods tend to overfit the training data in such situations, i.e. the method adjusts to very specific features of the training data, which are not characteristic for the considered property. This problem can be alleviated by diminishing the influence of unimportant, redundant or even misleading features. A better strategy is to eliminate such features completely. Ideally, a molecular property can be described by a small number of features that are chemically interpretable. The purpose of the present contribution is to provide a predictive modeling approach, which combines feature generation, feature selection, model building and control of overtraining into a single application called DemQSAR. DemQSAR is used to predict human volume of distribution (VD(ss)) and human clearance (CL). To control overtraining, quadratic and linear regularization terms were employed. A recursive feature selection approach is used to reduce the number of descriptors. The prediction performance is as good as the best predictions reported in the recent literature. The example presented here demonstrates that DemQSAR can generate a model that uses very few features while maintaining high predictive power. A standalone DemQSAR Java application for model building of any user defined property as well as a web interface for the prediction of human VD(ss) and CL is available on the webpage of DemPRED: http://agknapp.chemie.fu-berlin.de/dempred/ .

Stargate GTM: Bridging Descriptor and Activity Spaces.

PubMed

Gaspar, Héléna A; Baskin, Igor I; Marcou, Gilles; Horvath, Dragos; Varnek, Alexandre

2015-11-23

Predicting the activity profile of a molecule or discovering structures possessing a specific activity profile are two important goals in chemoinformatics, which could be achieved by bridging activity and molecular descriptor spaces. In this paper, we introduce the "Stargate" version of the Generative Topographic Mapping approach (S-GTM) in which two different multidimensional spaces (e.g., structural descriptor space and activity space) are linked through a common 2D latent space. In the S-GTM algorithm, the manifolds are trained simultaneously in two initial spaces using the probabilities in the 2D latent space calculated as a weighted geometric mean of probability distributions in both spaces. S-GTM has the following interesting features: (1) activities are involved during the training procedure; therefore, the method is supervised, unlike conventional GTM; (2) using molecular descriptors of a given compound as input, the model predicts a whole activity profile, and (3) using an activity profile as input, areas populated by relevant chemical structures can be detected. To assess the performance of S-GTM prediction models, a descriptor space (ISIDA descriptors) of a set of 1325 GPCR ligands was related to a B-dimensional (B = 1 or 8) activity space corresponding to pKi values for eight different targets. S-GTM outperforms conventional GTM for individual activities and performs similarly to the Lasso multitask learning algorithm, although it is still slightly less accurate than the Random Forest method.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rushton, Phillip S.; Olek, Anna T.; Makowski, Lee

The crystallographic structure of a rice (Oryza sativa) cellulose synthase, OsCesA8, plant-conserved region (P-CR), one of two unique domains in the catalytic domain of plant CesAs, was solved to 2.4 Å resolution. Two antiparallel α-helices form a coiled-coil domain linked by a large extended connector loop containing a conserved trio of aromatic residues. The P-CR structure was fit into a molecular envelope for the P-CR domain derived from small-angle X-ray scattering data. The P-CR structure and molecular envelope, combined with a homology-based chain trace of the CesA8 catalytic core, were modeled into a previously determined CesA8 small-angle X-ray scattering molecularmore » envelope to produce a detailed topological model of the CesA8 catalytic domain. The predicted position for the P-CR domain from the molecular docking models places the P-CR connector loop into a hydrophobic pocket of the catalytic core, with the coiled-coil aligned near the entrance of the substrate UDP-glucose into the active site. In this configuration, the P-CR coiled-coil alone is unlikely to regulate substrate access to the active site, but it could interact with other domains of CesA, accessory proteins, or other CesA catalytic domains to control substrate delivery.« less

Insights into the mechanism of C5aR inhibition by PMX53 via implicit solvent molecular dynamics simulations and docking

PubMed Central

2014-01-01

Background The complement protein C5a acts by primarily binding and activating the G-protein coupled C5a receptor C5aR (CD88), and is implicated in many inflammatory diseases. The cyclic hexapeptide PMX53 (sequence Ace-Phe-[Orn-Pro-dCha-Trp-Arg]) is a full C5aR antagonist of nanomolar potency, and is widely used to study C5aR function in disease. Results We construct for the first time molecular models for the C5aR:PMX53 complex without the a priori use of experimental constraints, via a computational framework of molecular dynamics (MD) simulations, docking, conformational clustering and free energy filtering. The models agree with experimental data, and are used to propose important intermolecular interactions contributing to binding, and to develop a hypothesis for the mechanism of PMX53 antagonism. Conclusion This work forms the basis for the design of improved C5aR antagonists, as well as for atomic-detail mechanistic studies of complement activation and function. Our computational framework can be widely used to develop GPCR-ligand structural models in membrane environments, peptidomimetics and other chemical compounds with potential clinical use. PMID:25170421

Combined QSAR and molecule docking studies on predicting P-glycoprotein inhibitors

NASA Astrophysics Data System (ADS)

Tan, Wen; Mei, Hu; Chao, Li; Liu, Tengfei; Pan, Xianchao; Shu, Mao; Yang, Li

2013-12-01

P-glycoprotein (P-gp) is an ATP-binding cassette multidrug transporter. The over expression of P-gp leads to the development of multidrug resistance (MDR), which is a major obstacle to effective treatment of cancer. Thus, designing effective P-gp inhibitors has an extremely important role in the overcoming MDR. In this paper, both ligand-based quantitative structure-activity relationship (QSAR) and receptor-based molecular docking are used to predict P-gp inhibitors. The results show that each method achieves good prediction performance. According to the results of tenfold cross-validation, an optimal linear SVM model with only three descriptors is established on 857 training samples, of which the overall accuracy (Acc), sensitivity, specificity, and Matthews correlation coefficient are 0.840, 0.873, 0.813, and 0.683, respectively. The SVM model is further validated by 418 test samples with the overall Acc of 0.868. Based on a homology model of human P-gp established, Surflex-dock is also performed to give binding free energy-based evaluations with the overall accuracies of 0.823 for the test set. Furthermore, a consensus evaluation is also performed by using these two methods. Both QSAR and molecular docking studies indicate that molecular volume, hydrophobicity and aromaticity are three dominant factors influencing the inhibitory activities.

A pilot study assessing the value of 3D printed molecular modelling tools for pharmacy student education.

PubMed

Hall, Susan; Grant, Gary; Arora, Devinder; Karaksha, Abdullah; McFarland, Amelia; Lohning, Anna; Anoopkumar-Dukie, Shailendra

2017-07-01

Medicinal chemistry and pharmacology are difficult topics to both teach and learn given the complex nature of drug mechanisms and drug-receptor interactions. This highlights the need for innovative teaching methods to deliver this information to students. One such method is through three-dimensional (3D) printing of enzymes and ligands in the teaching of molecular modelling concepts relating to drug-receptor and enzyme interactions be ligands. This type of printing has been shown to be beneficial in several educational settings; however, to our knowledge, its effectiveness in pharmacy, medicinal chemistry and pharmacology learning and teaching is largely unknown. Therefore, the aim of this study was to evaluate pharmacy student perceptions and the educational benefits of 3D printed molecules in molecular modelling with regards to engagement and learning outcomes when used in a drug-target interaction topic. This aim was achieved through administering students a short questionnaire designed to evaluate their engagement and learning outcomes with students also free to provide comments. This study found that nearly all (>90%) students found the activity was useful in improving both student engagement and learning outcomes. In conclusion, 3D printing may provide an alternative learning activity to help pharmacy students understand the drug-target interaction. Copyright © 2017 Elsevier Inc. All rights reserved.

The Extracellular Surface of the GLP-1 Receptor Is a Molecular Trigger for Biased Agonism.

PubMed

Wootten, Denise; Reynolds, Christopher A; Smith, Kevin J; Mobarec, Juan C; Koole, Cassandra; Savage, Emilia E; Pabreja, Kavita; Simms, John; Sridhar, Rohan; Furness, Sebastian G B; Liu, Mengjie; Thompson, Philip E; Miller, Laurence J; Christopoulos, Arthur; Sexton, Patrick M

2016-06-16

Ligand-directed signal bias offers opportunities for sculpting molecular events, with the promise of better, safer therapeutics. Critical to the exploitation of signal bias is an understanding of the molecular events coupling ligand binding to intracellular signaling. Activation of class B G protein-coupled receptors is driven by interaction of the peptide N terminus with the receptor core. To understand how this drives signaling, we have used advanced analytical methods that enable separation of effects on pathway-specific signaling from those that modify agonist affinity and mapped the functional consequence of receptor modification onto three-dimensional models of a receptor-ligand complex. This yields molecular insights into the initiation of receptor activation and the mechanistic basis for biased agonism. Our data reveal that peptide agonists can engage different elements of the receptor extracellular face to achieve effector coupling and biased signaling providing a foundation for rational design of biased agonists. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Comparative Molecular Dynamics Simulations of Mitogen-Activated Protein Kinase-Activated Protein Kinase 5

PubMed Central

Lindin, Inger; Wuxiuer, Yimingjiang; Ravna, Aina Westrheim; Moens, Ugo; Sylte, Ingebrigt

2014-01-01

The mitogen-activated protein kinase-activated protein kinase MK5 is a substrate of the mitogen-activated protein kinases p38, ERK3 and ERK4. Cell culture and animal studies have demonstrated that MK5 is involved in tumour suppression and promotion, embryogenesis, anxiety, cell motility and cell cycle regulation. In the present study, homology models of MK5 were used for molecular dynamics (MD) simulations of: (1) MK5 alone; (2) MK5 in complex with an inhibitor; and (3) MK5 in complex with the interaction partner p38α. The calculations showed that the inhibitor occupied the active site and disrupted the intramolecular network of amino acids. However, intramolecular interactions consistent with an inactive protein kinase fold were not formed. MD with p38α showed that not only the p38 docking region, but also amino acids in the activation segment, αH helix, P-loop, regulatory phosphorylation region and the C-terminal of MK5 may be involved in forming a very stable MK5-p38α complex, and that p38α binding decreases the residual fluctuation of the MK5 model. Electrostatic Potential Surface (EPS) calculations of MK5 and p38α showed that electrostatic interactions are important for recognition and binding. PMID:24651460

Integrated Molecular Characterization of Gastrointestinal Stromal Tumors (GIST) Harboring the Rare D842V Mutation in PDGFRA Gene

PubMed Central

Astolfi, Annalisa; Patterson, Janice; Nannini, Margherita; Saponara, Maristella; Gatto, Lidia; Santini, Donatella; do Valle, Italo F.; Castellani, Gastone; Fiorentino, Michelangelo; von Mehren, Margaret; Brandi, Giovanni; Biasco, Guido; Heinrich, Michael C.; Pantaleo, Maria Abbondanza

2018-01-01

Gastrointestinal stromal tumors (GIST) carrying the D842V activating mutation in the platelet-derived growth factor receptor alpha (PDGFRA) gene are a very rare subgroup of GIST (about 10%) known to be resistant to conventional tyrosine kinase inhibitors (TKIs) and to show an indolent behavior. In this study, we performed an integrated molecular characterization of D842V mutant GIST by whole-transcriptome and whole-exome sequencing coupled with protein–ligand interaction modelling to identify the molecular signature and any additional recurrent genomic event related to their clinical course. We found a very specific gene expression profile of D842V mutant tumors showing the activation of G-protein-coupled receptor (GPCR) signaling and a relative downregulation of cell cycle processes. Beyond D842V, no recurrently mutated genes were found in our cohort. Nevertheless, many private, clinically relevant alterations were found in each tumor (TP53, IDH1, FBXW7, SDH-complex). Molecular modeling of PDGFRA D842V suggests that the mutant protein binds imatinib with lower affinity with respect to wild-type structure, showing higher stability during the interaction with other type I TKIs (like crenolanib). D842V mutant GIST do not show any actionable recurrent molecular events of therapeutic significance, therefore this study supports the rationale of novel TKIs development that are currently being evaluated in clinical studies for the treatment of D842V mutant GIST. PMID:29510530

Wavelength and intensity dependence of recollision-enhanced multielectron effects in high-order harmonic generation

NASA Astrophysics Data System (ADS)

Abanador, Paul M.; Mauger, François; Lopata, Kenneth; Gaarde, Mette B.; Schafer, Kenneth J.

2018-04-01

Using a model molecular system (A2) with two active electrons restricted to one dimension, we examine high-order harmonic generation (HHG) enhanced by rescattering. Our results show that even at intensities well below the single ionization saturation, harmonics generated from the cation (A2+ ) can be significantly enhanced due to the rescattering of the electron that is initially ionized. This two-electron effect is manifested by the appearance of a secondary plateau and cutoff in the HHG spectrum, extending beyond the predicted cutoff in the single active electron approximation. We use our molecular model to investigate the wavelength dependence of rescattering enhanced HHG, which was first reported in a model atomic system [I. Tikhomirov, T. Sato, and K. L. Ishikawa, Phys. Rev. Lett. 118, 203202 (2017), 10.1103/PhysRevLett.118.203202]. We demonstrate that the HHG yield in the secondary cutoff is highly sensitive to the available electron rescattering energies as indicated by a dramatic scaling with respect to driving wavelength.

Structural refinement of the hERG1 pore and voltage-sensing domains with ROSETTA-membrane and molecular dynamics simulations.

PubMed

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.

Identification of Leishmania donovani Topoisomerase 1 inhibitors via intuitive scaffold hopping and bioisosteric modification of known Top 1 inhibitors

NASA Astrophysics Data System (ADS)

Mamidala, Rajinikanth; Majumdar, Papiya; Jha, Kunal Kumar; Bathula, Chandramohan; Agarwal, Rahul; Chary, M. Thirumala; Mazumdar, H. K.; Munshi, Parthapratim; Sen, Subhabrata

2016-05-01

A library of arylidenefuropyridinediones was discovered as potent inhibitors of Leishmania donovani Topoisomerase 1 (LdTop1) where the active molecules displayed considerable inhibition with single digit micromolar EC50 values. This molecular library was designed via intuitive scaffold hopping and bioisosteric modification of known topoisomerase 1 inhibitors such as camptothecin, edotecarin and etc. The design was rationalized by molecular docking analysis of the compound prototype with human topoisomerase 1 (HTop1) and Leishmania donovani topoisomerase 1(LdTop1). The most active compound 4 displayed no cytotoxicity against normal mammalian COS7 cell line (~100 fold less inhibition at the EC50). Similar to camptothecin, 4 interacted with free LdTop1 as observed in the preincubation DNA relaxation inhibition experiment. It also displayed anti-protozoal activity against Leishmania donovani promastigote. Crystal structure investigation of 4 and its molecular modelling with LdTop1 revealed putative binding sites in the enzyme that could be harnessed to generate molecules with better potency.

A phenylalanine rotameric switch for signal-state control in bacterial chemoreceptors

NASA Astrophysics Data System (ADS)

Ortega, Davi R.; Yang, Chen; Ames, Peter; Baudry, Jerome; Parkinson, John S.; Zhulin, Igor B.

2013-12-01

Bacterial chemoreceptors are widely used as a model system for elucidating the molecular mechanisms of transmembrane signalling and have provided a detailed understanding of how ligand binding by the receptor modulates the activity of its associated kinase CheA. However, the mechanisms by which conformational signals move between signalling elements within a receptor dimer and how they control kinase activity remain unknown. Here, using long molecular dynamics simulations, we show that the kinase-activating cytoplasmic tip of the chemoreceptor fluctuates between two stable conformations in a signal-dependent manner. A highly conserved residue, Phe396, appears to serve as the conformational switch, because flipping of the stacked aromatic rings of an interacting F396-F396‧ pair in the receptor homodimer takes place concomitantly with the signal-related conformational changes. We suggest that interacting aromatic residues, which are common stabilizers of protein tertiary structure, might serve as rotameric molecular switches in other biological processes as well.

A Low-Molecular-Weight Antagonist for the Human Thyrotropin Receptor with Therapeutic Potential for Hyperthyroidism

PubMed Central

Neumann, Susanne; Kleinau, Gunnar; Costanzi, Stefano; Moore, Susanna; Jiang, Jian-kang; Raaka, Bruce M.; Thomas, Craig J.; Krause, Gerd; Gershengorn, Marvin C.

2008-01-01

Low-molecular-weight (LMW) antagonists for TSH receptor (TSHR) may have therapeutic potential as orally active drugs to block stimulating antibodies (TsAbs) in Graves’ hyperthyroidism. We describe an approach to identify LMW ligands for TSHR based on Org41841, a LMW partial agonist for the LH/choriogonadotropin receptor and TSHR. We used molecular modeling and functional experiments to guide the chemical modification of Org41841. We identified an antagonist (NIDDK/CEB-52) that selectively inhibits activation of TSHR by both TSH and TsAbs. Whereas initially characterized in cultured cells overexpressing TSHRs, the antagonist was also active under more physiologically relevant conditions in primary cultures of human thyrocytes expressing endogenous TSHRs in which it inhibited TSH- and TsAb-induced up-regulation of mRNA transcripts for thyroperoxidase. Our results establish this LMW compound as a lead for the development of higher potency antagonists and serve as proof of principle that LMW ligands that target TSHR could serve as drugs in patients with Graves’ disease. PMID:18669595

Cluster model studies of anion and molecular specificities via electrospray ionization photoelectron spectroscopy

DOE PAGES

Wang, Xue -Bin

2017-01-06

Ion specificity, a widely observed macroscopic phenomenon in condensed phases and at interfaces, is essentially a fundamental chemical physical issue. We have been investigating such effects using cluster models in an “atom-by-atom” and “molecule-by-molecule” fashion not possible with condensed-phase methods. We use electrospray ionization (ESI) to generate molecular and ionic clusters to simulate key molecular entities involved in local binding regions, and characterize them employing negative ion photoelectron spectroscopy (NIPES). Inter- and intramolecular interactions and binding configurations are directly obtained as functions of cluster size and composition, providing insightful molecular-level description and characterization over the local active sites that playmore » crucial roles in determining solution chemistry and condensed phase phenomena. Finally, the topics covered in this article are relevant to a wide scope of research fields ranging from ion specific effects in electrolyte solutions, ion selectivity/recognition in normal functioning of life, to molecular specificity in aerosol particle formation, as well as in rational material design and synthesis.« less

Generative Recurrent Networks for De Novo Drug Design.

PubMed

Gupta, Anvita; Müller, Alex T; Huisman, Berend J H; Fuchs, Jens A; Schneider, Petra; Schneider, Gisbert

2018-01-01

Generative artificial intelligence models present a fresh approach to chemogenomics and de novo drug design, as they provide researchers with the ability to narrow down their search of the chemical space and focus on regions of interest. We present a method for molecular de novo design that utilizes generative recurrent neural networks (RNN) containing long short-term memory (LSTM) cells. This computational model captured the syntax of molecular representation in terms of SMILES strings with close to perfect accuracy. The learned pattern probabilities can be used for de novo SMILES generation. This molecular design concept eliminates the need for virtual compound library enumeration. By employing transfer learning, we fine-tuned the RNN's predictions for specific molecular targets. This approach enables virtual compound design without requiring secondary or external activity prediction, which could introduce error or unwanted bias. The results obtained advocate this generative RNN-LSTM system for high-impact use cases, such as low-data drug discovery, fragment based molecular design, and hit-to-lead optimization for diverse drug targets. © 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

Design, synthesis, antiviral activity and three-dimensional quantitative structure-activity relationship study of novel 1,4-pentadien-3-one derivatives containing the 1,3,4-oxadiazole moiety.

PubMed

Gan, Xiuhai; Hu, Deyu; Li, Pei; Wu, Jian; Chen, Xuewen; Xue, Wei; Song, Baoan

2016-03-01

1,4-Pentadien-3-one and 1,3,4-oxadiazole derivatives possess good antiviral activities, and their substructure units are usually used in antiviral agent design. In order to discover novel molecules with high antiviral activities, a series of 1,4-pentadien-3-one derivatives containing the 1,3,4-oxadiazole moiety were designed and synthesised. Bioassays showed that most of the title compounds exhibited good inhibitory activities against tobacco mosaic virus (TMV) in vivo. The compound 8f possessing the best protective activity against TMV had an EC50 value of 135.56 mg L(-1) , which was superior to that of ribavirin (435.99 mg L(-1) ). Comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) techniques were used in three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of protective activities, with values of q(2) and r(2) for the CoMFA and CoMSIA models of 0.751 and 0.775 and 0.936 and 0.925 respectively. Compound 8k with higher protective activity (EC50 = 123.53 mg L(-1) ) according to bioassay was designed and synthesised on the basis of the 3D-QSAR models. Some of the title compounds displayed good antiviral activities. 3D-QSAR models revealed that the appropriate compact electron-withdrawing and hydrophobic group at the benzene ring could enhance antiviral activity. These results could provide important structural insights for the design of highly active 1,4-pentadien-3-one derivatives. © 2015 Society of Chemical Industry.

Reactivity of bromoalkanes in reactions of coordinated molecular decay

NASA Astrophysics Data System (ADS)

Pokidova, T. S.; Denisov, E. T.

2016-09-01

The results from experiments on reactions of the coordinated molecular decay of RBr bromoalkanes on olefin and HBr are analyzed using the model of intersecting parabolas (MIP). Kinetic parameters within the MIP are calculated from the experimental data, enabling calculation of the activation energies ( E) and rate constants ( k) of such reactions, based on the enthalphy of the reaction and the MIP algorithms. The factors affecting the E of the RBr decay reaction are established: the enthalphy of the reaction, triplet repulsion, the energy of radical R• stabilization, the presence of a π bond adjacent to the reaction center, and the dipole-dipole interaction of polar groups. The energy spectrum of the partial energies of activation is constructed for the reaction of coordinated molecular decay of RBr, and the E and k of inverse addition reactions are evaluated.

Chemical Structure-Biological Activity Models for Pharmacophores’ 3D-Interactions

PubMed Central

Putz, Mihai V.; Duda-Seiman, Corina; Duda-Seiman, Daniel; Putz, Ana-Maria; Alexandrescu, Iulia; Mernea, Maria; Avram, Speranta

2016-01-01

Within medicinal chemistry nowadays, the so-called pharmaco-dynamics seeks for qualitative (for understanding) and quantitative (for predicting) mechanisms/models by which given chemical structure or series of congeners actively act on biological sites either by focused interaction/therapy or by diffuse/hazardous influence. To this aim, the present review exposes three of the fertile directions in approaching the biological activity by chemical structural causes: the special computing trace of the algebraic structure-activity relationship (SPECTRAL-SAR) offering the full analytical counterpart for multi-variate computational regression, the minimal topological difference (MTD) as the revived precursor for comparative molecular field analyses (CoMFA) and comparative molecular similarity indices analysis (CoMSIA); all of these methods and algorithms were presented, discussed and exemplified on relevant chemical medicinal systems as proton pump inhibitors belonging to the 4-indolyl,2-guanidinothiazole class of derivatives blocking the acid secretion from parietal cells in the stomach, the 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thymine congeners’ (HEPT ligands) antiviral activity against Human Immunodeficiency Virus of first type (HIV-1) and new pharmacophores in treating severe genetic disorders (like depression and psychosis), respectively, all involving 3D pharmacophore interactions. PMID:27399692

QSAR Study on the anti-tumor activity of levofloxacin-thiadiazole HDACi conjugates

NASA Astrophysics Data System (ADS)

Tang, Ziqiang; Feng, Hui; Chen, Yan; Yue, Wei; Feng, Changjun

2017-12-01

A molecular electronegativity distance vector(M t) based on 13atomic types is used to describe the structures of 19 conjugates(LHCc) of levofloxacin-thiadiazole HDAC inhibitor(HDACi) and related to the anti-tumor activity (M F and P C) of LHCc against MCF-7 and PC-3. The quantitative structure-activity relationships (QSAR) was established by using leaps-and-bounds regression analysis for the anti-tumor activities (M F and P C) of 19 above compounds to MCF-7and PC-3 along with the M t. The correlation coefficients (R 2) and the leave-one-out (LOO) cross validation R cv 2 for the M F and P C models were 0.792 and 0.679; 0.773 and 0.565, respectively. The QSAR models have favorable correlation, as well as robustness and good prediction capability by R 2, F, R cv 2, A IC F IT V IF tests. The results indicate that the molecular structural units: －CHg－(g=1, 2), －NH2, －NH－,－OH, O=, －O－, －S－ and －X are main factors which can affect the anti-tumor activity M F and PC bioactivities of these compounds directly.

Modeling meiotic chromosome pairing: nuclear envelope attachment, telomere-led active random motion, and anomalous diffusion

PubMed Central

Marshall, Wallace F.; Fung, Jennifer C.

2016-01-01

The recognition and pairing of homologous chromosomes during meiosis is a complex physical and molecular process involving a combination of polymer dynamics and molecular recognition events. Two highly conserved features of meiotic chromosome behavior are the attachment of telomeres to the nuclear envelope and the active random motion of telomeres driven by their interaction with cytoskeletal motor proteins. Both of these features have been proposed to facilitate the process of homolog pairing, but exactly what role these features play in meiosis remains poorly understood. Here we investigate the roles of active motion and nuclear envelope tethering using a Brownian dynamics simulation in which meiotic chromosomes are represented by a Rouse polymer model subjected to tethering and active forces at the telomeres. We find that tethering telomeres to the nuclear envelope slows down pairing relative to the rates achieved by un-attached chromosomes, but that randomly-directed active forces applied to the telomeres speeds up pairing dramatically in a manner that depends on the statistical properties of the telomere force fluctuations. The increased rate of initial pairing cannot be explained by stretching out of the chromosome conformation but instead seems to correlate with anomalous diffusion of sub-telomeric regions. PMID:27046097

Modeling meiotic chromosome pairing: nuclear envelope attachment, telomere-led active random motion, and anomalous diffusion

NASA Astrophysics Data System (ADS)

Marshall, Wallace F.; Fung, Jennifer C.

2016-04-01

The recognition and pairing of homologous chromosomes during meiosis is a complex physical and molecular process involving a combination of polymer dynamics and molecular recognition events. Two highly conserved features of meiotic chromosome behavior are the attachment of telomeres to the nuclear envelope and the active random motion of telomeres driven by their interaction with cytoskeletal motor proteins. Both of these features have been proposed to facilitate the process of homolog pairing, but exactly what role these features play in meiosis remains poorly understood. Here we investigate the roles of active motion and nuclear envelope tethering using a Brownian dynamics simulation in which meiotic chromosomes are represented by a Rouse polymer model subjected to tethering and active forces at the telomeres. We find that tethering telomeres to the nuclear envelope slows down pairing relative to the rates achieved by unattached chromosomes, but that randomly directed active forces applied to the telomeres speed up pairing dramatically in a manner that depends on the statistical properties of the telomere force fluctuations. The increased rate of initial pairing cannot be explained by stretching out of the chromosome conformation but instead seems to correlate with anomalous diffusion of sub-telomeric regions.

New Coumarin Derivatives as Potent Selective COX-2 Inhibitors: Synthesis, Anti-Inflammatory, QSAR, and Molecular Modeling Studies.

PubMed

Dawood, Dina H; Batran, Rasha Z; Farghaly, Thoraya A; Khedr, Mohammed A; Abdulla, Mohamed M

2015-12-01

Two new series of coumarin derivatives incorporating thiazoline and thiazolidinone moieties were designed, synthesized, and investigated in vivo for their anti-inflammatory activities using the carrageenan-induced rat paw edema model and in vitro for their inhibitory activities against the human cyclooxygenase (COX)-1 and COX-2 isoforms. Most of the synthesized compounds demonstrated exceptionally high in vivo anti-inflammatory activity and displayed superior GI safety profiles (0-7% ulceration) as compared to indomethacin. All the bioactive compounds showed in vitro high affinity and selectivity toward the COX-2 isoenzyme, compared to the reference celecoxib with IC50 values ranging from 0.31 to 0.78 μM. The ethyl thiosemicarbazone 2b, thiazoline derivatives 3a, 3b, 5b, 6a, and 7f, and the thiazolidinone compounds 8b and 9a showed the highest in vivo and in vitro anti-inflammatory activities with remarkable COX-2 selectivity. Quantitative structure-activity relationship study (QSAR) was done and resulted in a highly predictive power R(2) (0.908). A molecular docking study revealed a relationship between the docking affinity and the biological results. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

An interactive human carbonic anhydrase-II (hCA-II) receptor--pharmacophore molecular model & anti-convulsant activity of the designed and synthesized 5-amino-1,3,4-thiadiazole-2-thiol conjugated imine derivatives.

PubMed

Yusuf, Mohammad; Khan, Riaz A; Khan, Maria; Ahmed, Bahar

2013-05-01

New imines, derived from aromatic aldehyde, chalcones and 5-amino-1,3,4-thiadiazole-2-thiol exhibited promising anti-convulsant activity which is explained through chemo-biological interactions at receptor site producing the inhibition of human Carbonic Anhydrase-II enzyme (hCA-II) through the proposed pharmacophore model at molecular levels as basis for pharmacological activity. The compounds 5-{1-(4-Chlorophenyl)-3-[4-(methoxy-phenyl)-prop-2-en-1-ylidene]amino}-1,3,4-thiadiazole-2-thiol (2b), 5-{[1-(4-chloro-phenyl)]-3-[4-(dimethyl-amino-phenyl)-prop-2-en-1-ylidene]amino}-1,3,4-thiadiazole-2-thiol (2c) and 5-{[1-(4-chloro-phenyl)]-3-[(4-amino-phenyl)-prop-2-en-1-ylidene]amino}-1,3,4-thiadiazole-2-thiol (2f) showed 100% activity in comparison with standard Acetazolamide, a known anti-convulsant drug. The compounds 2c, 2f also passed the Rotarod and Ethanol Potentiation tests which further confirmed them to be safe in motor coordination activity and safe from generating neurological toxicity. © 2013 John Wiley & Sons A/S.

Constant pH Molecular Dynamics of Proteins in Explicit Solvent with Proton Tautomerism

PubMed Central

Goh, Garrett B.; Hulbert, Benjamin S.; Zhou, Huiqing; Brooks, Charles L.

2015-01-01

pH is a ubiquitous regulator of biological activity, including protein-folding, protein-protein interactions and enzymatic activity. Existing constant pH molecular dynamics (CPHMD) models that were developed to address questions related to the pH-dependent properties of proteins are largely based on implicit solvent models. However, implicit solvent models are known to underestimate the desolvation energy of buried charged residues, increasing the error associated with predictions that involve internal ionizable residue that are important in processes like hydrogen transport and electron transfer. Furthermore, discrete water and ions cannot be modeled in implicit solvent, which are important in systems like membrane proteins and ion channels. We report on an explicit solvent constant pH molecular dynamics framework based on multi-site λ-dynamics (CPHMDMSλD). In the CPHMDMSλD framework, we performed seamless alchemical transitions between protonation and tautomeric states using multi-site λ-dynamics, and designed novel biasing potentials to ensure that the physical end-states are predominantly sampled. We show that explicit solvent CPHMDMSλD simulations model realistic pH-dependent properties of proteins such as the Hen-Egg White Lysozyme (HEWL), binding domain of 2-oxoglutarate dehydrogenase (BBL) and N-terminal domain of ribosomal L9 (NTL9), and the pKa predictions are in excellent agreement with experimental values, with a RMSE ranging from 0.72 to 0.84 pKa units. With the recent development of the explicit solvent CPHMDMSλD framework for nucleic acids, accurate modeling of pH-dependent properties of both major class of biomolecules – proteins and nucleic acids is now possible. PMID:24375620

An orientation sensitive approach in biomolecule interaction quantitative structure-activity relationship modeling and its application in ion-exchange chromatography.

PubMed

Kittelmann, Jörg; Lang, Katharina M H; Ottens, Marcel; Hubbuch, Jürgen

2017-01-27

Quantitative structure-activity relationship (QSAR) modeling for prediction of biomolecule parameters has become an established technique in chromatographic purification process design. Unfortunately available descriptor sets fail to describe the orientation of biomolecules and the effects of ionic strength in the mobile phase on the interaction with the stationary phase. The literature describes several special descriptors used for chromatographic retention modeling, all of these do not describe the screening of electrostatic potential by the mobile phase in use. In this work we introduce two new approaches of descriptor calculations, namely surface patches and plane projection, which capture an oriented binding to charged surfaces and steric hindrance of the interaction with chromatographic ligands with regard to electrostatic potential screening by mobile phase ions. We present the use of the developed descriptor sets for predictive modeling of Langmuir isotherms for proteins at different pH values between pH 5 and 10 and varying ionic strength in the range of 10-100mM. The resulting model has a high correlation of calculated descriptors and experimental results, with a coefficient of determination of 0.82 and a predictive coefficient of determination of 0.92 for unknown molecular structures and conditions. The agreement of calculated molecular interaction orientations with both, experimental results as well as molecular dynamic simulations from literature is shown. The developed descriptors provide the means for improved QSAR models of chromatographic processes, as they reflect the complex interactions of biomolecules with chromatographic phases. Copyright © 2016 Elsevier B.V. All rights reserved.

Molecular pathophysiology of cerebral edema

PubMed Central

Gerzanich, Volodymyr; Simard, J Marc

2015-01-01

Advancements in molecular biology have led to a greater understanding of the individual proteins responsible for generating cerebral edema. In large part, the study of cerebral edema is the study of maladaptive ion transport. Following acute CNS injury, cells of the neurovascular unit, particularly brain endothelial cells and astrocytes, undergo a program of pre- and post-transcriptional changes in the activity of ion channels and transporters. These changes can result in maladaptive ion transport and the generation of abnormal osmotic forces that, ultimately, manifest as cerebral edema. This review discusses past models and current knowledge regarding the molecular and cellular pathophysiology of cerebral edema. PMID:26661240

Green leaf volatiles, fire and nonanoic acid activate MAPkinases in the model grass species Lolium temulentum

USDA-ARS?s Scientific Manuscript database

Forage and turf related grasses are utilized in diverse environments where they are routinely subjected to herbicides and exposed to fire and volatiles after cutting, however very little is known concerning the perception or molecular responses to these different stresses or compounds. In the model ...

Elucidation of chemosensitization effect of acridones in cancer cell lines: Combined pharmacophore modeling, 3D QSAR, and molecular dynamics studies.

PubMed

Gade, Deepak Reddy; Makkapati, Amareswararao; Yarlagadda, Rajesh Babu; Peters, Godefridus J; Sastry, B S; Rajendra Prasad, V V S

2018-06-01

Overexpression of P-glycoprotein (P-gp) leads to the emergence of multidrug resistance (MDR) in cancer treatment. Acridones have the potential to reverse MDR and sensitize cells. In the present study, we aimed to elucidate the chemosensitization potential of acridones by employing various molecular modelling techniques. Pharmacophore modeling was performed for the dataset of chemosensitizing acridones earlier proved for cytotoxic activity against MCF7 breast cancer cell line. Gaussian-based QSAR studies also performed to predict the favored and disfavored region of the acridone molecules. Molecular dynamics simulations were performed for compound 10 and human P-glycoprotein (obtained from Homology modeling). An efficient pharmacophore containing 2 hydrogen bond acceptors and 3 aromatic rings (AARRR.14) was identified. NCI 2012 chemical database was screened against AARRR.14 CPH and identified 25 best-fit molecules. Potential regions of the compound were identified through Field (Gaussian) based QSAR. Regression analysis of atom-based QSAR resulted in r 2 of 0.95 and q 2 of 0.72, whereas, regression analysis of field-based QSAR resulted in r 2 of 0.92 and q 2 of 0.87 along with r 2 cv as 0.71. The fate of the acridone molecule (compound 10) in the P-glycoprotein environment is analyzed through analyzing the conformational changes occurring during the molecular dynamics simulations. Combined data of different in silico techniques provided basis for deeper understanding of structural and mechanistic insights of interaction phenomenon of acridones with P-glycoprotein and also as strategic basis for designing more potent molecules for anti-cancer and multidrug resistance reversal activities. Copyright © 2018 Elsevier Ltd. All rights reserved.

GPCR-ModSim: A comprehensive web based solution for modeling G-protein coupled receptors

PubMed Central

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

QSAR Study of p56lck Protein Tyrosine Kinase Inhibitory Activity of Flavonoid Derivatives Using MLR and GA-PLS

PubMed Central

Fassihi, Afshin; Sabet, Razieh

2008-01-01

Quantitative relationships between molecular structure and p56lck protein tyrosine kinase inhibitory activity of 50 flavonoid derivatives are discovered by MLR and GA-PLS methods. Different QSAR models revealed that substituent electronic descriptors (SED) parameters have significant impact on protein tyrosine kinase inhibitory activity of the compounds. Between the two statistical methods employed, GA-PLS gave superior results. The resultant GA-PLS model had a high statistical quality (R2 = 0.74 and Q2 = 0.61) for predicting the activity of the inhibitors. The models proposed in the present work are more useful in describing QSAR of flavonoid derivatives as p56lck protein tyrosine kinase inhibitors than those provided previously. PMID:19325836

Electron-density descriptors as predictors in quantitative structure--activity/property relationships and drug design.

PubMed

Matta, Chérif F; Arabi, Alya A

2011-06-01

The use of electron density-based molecular descriptors in drug research, particularly in quantitative structure--activity relationships/quantitative structure--property relationships studies, is reviewed. The exposition starts by a discussion of molecular similarity and transferability in terms of the underlying electron density, which leads to a qualitative introduction to the quantum theory of atoms in molecules (QTAIM). The starting point of QTAIM is the topological analysis of the molecular electron-density distributions to extract atomic and bond properties that characterize every atom and bond in the molecule. These atomic and bond properties have considerable potential as bases for the construction of robust quantitative structure--activity/property relationships models as shown by selected examples in this review. QTAIM is applicable to the electron density calculated from quantum-chemical calculations and/or that obtained from ultra-high resolution x-ray diffraction experiments followed by nonspherical refinement. Atomic and bond properties are introduced followed by examples of application of each of these two families of descriptors. The review ends with a study whereby the molecular electrostatic potential, uniquely determined by the density, is used in conjunction with atomic properties to elucidate the reasons for the biological similarity of bioisosteres.

Development of Continuum-Atomistic Approach for Modeling Metal Irradiation by Heavy Ions

NASA Astrophysics Data System (ADS)

Batgerel, Balt; Dimova, Stefka; Puzynin, Igor; Puzynina, Taisia; Hristov, Ivan; Hristova, Radoslava; Tukhliev, Zafar; Sharipov, Zarif

2018-02-01

Over the last several decades active research in the field of materials irradiation by high-energy heavy ions has been worked out. The experiments in this area are labor-consuming and expensive. Therefore the improvement of the existing mathematical models and the development of new ones based on the experimental data of interaction of high-energy heavy ions with materials are of interest. Presently, two approaches are used for studying these processes: a thermal spike model and molecular dynamics methods. The combination of these two approaches - the continuous-atomistic model - will give the opportunity to investigate more thoroughly the processes of irradiation of materials by high-energy heavy ions. To solve the equations of the continuous-atomistic model, a software package was developed and the block of molecular dynamics software was tested on the heterogeneous cluster HybriLIT.

Synthesis, biological activity and molecular modeling study of new Schiff bases incorporated with indole moiety.

PubMed

Halawa, Ahmed H; El-Gilil, Shimaa Mohamed Abd; Bedair, Ahmed H; Shaaban, Mohamed; Frese, Marcel; Sewald, Norbert; Eliwa, Essam M; El-Agrody, Ahmed M

2017-10-26

A new series of heterocyclic Schiff bases 2-9 containing indole moiety were synthesized by facile and efficient condensation of indole-3/2/5-carboxaldehyde (1a/1b/1c) with different aromatic and heterocyclic primary amines using conventional and/or microwave irradiation methods. The structures of the obtained compounds were assigned by sophisticated spectroscopic and spectrometric techniques (1D-NMR, 2D-NMR and MS). The synthesized compounds were screened for their cytotoxicity and antibacterial activities. In vitro cytotoxicity screening revealed that compound 5 exhibited moderate activity against KB-3-1 cell line (IC50=57.7 μM) while 5-indolylimino derivative 7 indicated close to the activity (IC50=19.6 μM) in comparison with the positive control (+)-Griseofulvin (IC50=19.2 μM), while the tested compounds 5, 6b, 7 and 9 revealed good or moderate antibacterial activity. In addition, molecular docking study of Schiff bases 2-9 was performed by Molecular Operating Environment (MOE 2014.09) program on the matrix metalloproteinase-8 (MMP-8) (Protein Data Bank (PDB) ID: 1MNC) in an attempt to explore their mode of action as anticancer drugs.

Modelling vibrational coherence in the primary rhodopsin photoproduct.

PubMed

Weingart, O; Garavelli, M

2012-12-14

Molecular dynamics simulations of the rhodopsin photoreaction reveal coherent low frequency oscillations in the primary photoproduct (photorhodopsin), with frequencies slightly higher than observed in the experiment. The coherent molecular motions in the batho-precursor can be attributed to the activation of ground state vibrational modes in the hot photo-product, involving out-of-plane deformations of the carbon skeleton. Results are discussed and compared with respect to spectroscopic data and suggested reaction mechanisms.

Synthesis, molecular modelling, and preliminary anticonvulsant activity evaluation of novel naphthalen-2-yl acetate and 1,6-dithia-4,9-diazaspiro [4.4] nonane-3,8-dione derivatives.

PubMed

Ghareb, Nagat; Abdel Daim, Mohamed M; El-Sayed, Norhan M; Elgawish, Mohamed Saleh

2017-04-01

The synthesis, pharmacological evaluation and molecular modelling study of novel naphthalen-2-yl acetate and 1,6-dithia-4,9-diazaspiro [4.4]nonane-3,8-dione derivatives as potential anticonvulsant agents are described. The newly synthesized compounds were characterized by both analytical and spectral data. Alkylation of 1H-imidazole or substituted piperazine with 1-(2-naphthyl)-2-bromoethanone (2) gave naphthalen-2-yl 2-(1H-imidazol-1-yl) acetate (3) and naphthalen-2-yl 2-(substituted piperazin-1-yl) acetate (4-8). Moreover, condensation of naphthalen-2-yl 2-bromoacetate or 2-bromo-1-(naphthalen-2-yl) ethanone with hydrazine hydrate and acetylacetone resulted in the formation of the cyclic pyrazole products 9 and 13. Sonication of naphthalen-2-yl acetate (1) with 2-chloropyridine, 2-chloropyrimidine and 2-(chloromethyl) oxirane gave naphthalen-2-yl 2-(pyridin-2-yl) acetate (10), naphthalen-2-yl 2-(pyrimidin-2-yl) acetate (11) and naphthalen-2-yl-3-(oxiran-2-yl) propanoate (12) respectively. Cyclocondensation reaction of 2-iminothiazolidin-4-one (14) with thioglycolic acid, thiolactic acid and thiomalic acid gave 1,6-dithia-4,9-diazaspiro [4.4]nonane-3,8-dione derivatives (15-17). The compounds were testedin vivofor the anticonvulsant activity by delaying strychnine-induced seizures. The diazaspirononane (17) and 1-(2-naphthyl)-2-bromoethanone (2) showed a high significant delay in the onset of convulsion and prolongation of survival time compared to phenobarbital. The molecular modelling study of anticonvulsant activity of synthesized compounds showed a CNS depressant activity via modulation of benzodiazepine allosteric site in GABA-A receptors. Copyright © 2017 Elsevier Inc. All rights reserved.

Pharmacophore modeling, molecular docking, and molecular dynamics simulation approaches for identifying new lead compounds for inhibiting aldose reductase 2.

PubMed

Sakkiah, Sugunadevi; Thangapandian, Sundarapandian; Lee, Keun Woo

2012-07-01

Aldose reductase 2 (ALR2), which catalyzes the reduction of glucose to sorbitol using NADP as a cofactor, has been implicated in the etiology of secondary complications of diabetes. A pharmacophore model, Hypo1, was built based on 26 compounds with known ALR2-inhibiting activity values. Hypo1 contains important chemical features required for an ALR2 inhibitor, and demonstrates good predictive ability by having a high correlation coefficient (0.95) as well as the highest cost difference (128.44) and the lowest RMS deviation (1.02) among the ten pharmacophore models examined. Hypo1 was further validated by Fisher's randomization method (95%), test set (r = 0.91), and the decoy set shows the goodness of fit (0.70). Furthermore, during virtual screening, Hypo1 was used as a 3D query to screen the NCI database, and the hit leads were sorted by applying Lipinski's rule of five and ADME properties. The best-fitting leads were subjected to docking to identify a suitable orientation at the ALR2 active site. The molecule that showed the strongest interactions with the critical amino acids was used in molecular dynamics simulations to calculate its binding affinity to the candidate molecules. Thus, Hypo1 describes the key structure-activity relationship along with the estimated activities of ALR2 inhibitors. The hit molecules were searched against PubChem to find similar molecules with new scaffolds. Finally, four molecules were found to satisfy all of the chemical features and the geometric constraints of Hypo1, as well as to show good dock scores, PLPs and PMFs. Thus, we believe that Hypo1 facilitates the selection of novel scaffolds for ALR2, allowing new classes of ALR2 inhibitors to be designed.

Synthesis of model humic substances: a mechanistic study using controllable H/D exchange and Fourier transform ion cyclotron resonance mass spectrometry.

PubMed

Zherebker, Alexander Ya; Airapetyan, David; Konstantinov, Andrey I; Kostyukevich, Yury I; Kononikhin, Alexey S; Popov, Igor A; Zaitsev, Kirill V; Nikolaev, Eugene N; Perminova, Irina V

2015-07-07

The products of the oxidative coupling of phenols are frequently used as synthetic analogues to natural humic substances (HS) for biomedical research. However, their molecular compositions and exact structures remain largely unknown. The objective of this study was to develop a novel approach for the molecular-level analysis of phenolic polymerisates that is capable of inventorying molecular constituents and resolving their distinct structural formulas. For this purpose, we have synthesized the model HS using the oxidative coupling of a specifically designed phenylpropanoic monomer, 3-(4-hydroxy-3-methoxyphenyl)-3-oxopropionic acid, to hydroquinone. We have characterized the synthesized model HS using high resolution Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS), (1)H NMR spectroscopy, and controllable hydrogen/deuterium (H/D) exchange. We succeeded in the molecular inventory of the model HS. The assigned molecular formulas occupied the substantial space of CHO compositions in the Van Krevelen diagram with a maximum density found in the regions of tannins and lignins, resembling those of natural HS. To identify the exact structural formulas of the individual constituents in the model HS, we have applied selective H/D exchange of non-labile backbone protons by a choice of basic or acidic catalytic conditions followed by FTICR MS. The determined formulas allowed us to verify the proposed pathways of hydroxylation and carboxylation in the course of the phenolic coupling and to identify the acetylation of aromatic rings as an important side reaction. We conclude that the proposed analytical approach may be used to identify the molecular carriers of biological activity within the phenolic polymerisates and eventually within natural HS.

Reactivity of fluoroalkanes in reactions of coordinated molecular decomposition

NASA Astrophysics Data System (ADS)

Pokidova, T. S.; Denisov, E. T.

2017-08-01

Experimental results on the coordinated molecular decomposition of RF fluoroalkanes to olefin and HF are analyzed using the model of intersecting parabolas (IPM). The kinetic parameters are calculated to allow estimates of the activation energy ( E) and rate constant ( k) of these reactions, based on enthalpy and IPM algorithms. Parameters E and k are found for the first time for eight RF decomposition reactions. The factors that affect activation energy E of RF decomposition (the enthalpy of the reaction, the electronegativity of the atoms of reaction centers, and the dipole-dipole interaction of polar groups) are determined. The values of E and k for reverse reactions of addition are estimated.

AMPK modulatory activity of olive-tree leaves phenolic compounds: Bioassay-guided isolation on adipocyte model and in silico approach.

PubMed

Jiménez-Sánchez, Cecilia; Olivares-Vicente, Mariló; Rodríguez-Pérez, Celia; Herranz-López, María; Lozano-Sánchez, Jesús; Segura-Carretero, Antonio; Fernández-Gutiérrez, Alberto; Encinar, José Antonio; Micol, Vicente

2017-01-01

Olive-tree polyphenols have demonstrated potential for the management of obesity-related pathologies. We aimed to explore the capacity of Olive-tree leaves extract to modulate triglyceride accumulation and AMP-activated protein kinase activity (AMPK) on a hypertrophic adipocyte model. Intracellular triglycerides and AMPK activity were measured on the hypertrophic 3T3-L1 adipocyte model by AdipoRed and immunofluorescence microscopy, respectively. Reverse phase high performance liquid chromatography coupled to time-of-flight mass detection with electrospray ionization (RP-HPLC-ESI-TOF/MS) was used for the fractionation of the extract and the identification of the compounds. In-silico molecular docking of the AMPK alpha-2, beta and gamma subunits with the identified compounds was performed. Olive-tree leaves extract decreased the intracellular lipid accumulation through AMPK-dependent mechanisms in hypertrophic adipocytes. Secoiridoids, cinnamic acids, phenylethanoids and phenylpropanoids, flavonoids and lignans were the candidates predicted to account for this effect. Molecular docking revealed that some compounds may be AMPK-gamma modulators. The modulatory effects of compounds over the alpha and beta AMPK subunits appear to be less probable. Olive-tree leaves polyphenols modulate AMPK activity, which may become a therapeutic aid in the management of obesity-associated disturbances. The natural occurrence of these compounds may have important nutritional implications for the design of functional ingredients.

AMPK modulatory activity of olive–tree leaves phenolic compounds: Bioassay-guided isolation on adipocyte model and in silico approach

PubMed Central

Jiménez-Sánchez, Cecilia; Olivares-Vicente, Mariló; Rodríguez-Pérez, Celia; Herranz-López, María; Lozano-Sánchez, Jesús; Segura-Carretero, Antonio; Fernández-Gutiérrez, Alberto; Encinar, José Antonio; Micol, Vicente

2017-01-01

Scope Olive-tree polyphenols have demonstrated potential for the management of obesity-related pathologies. We aimed to explore the capacity of Olive-tree leaves extract to modulate triglyceride accumulation and AMP-activated protein kinase activity (AMPK) on a hypertrophic adipocyte model. Methods Intracellular triglycerides and AMPK activity were measured on the hypertrophic 3T3-L1 adipocyte model by AdipoRed and immunofluorescence microscopy, respectively. Reverse phase high performance liquid chromatography coupled to time-of-flight mass detection with electrospray ionization (RP-HPLC-ESI-TOF/MS) was used for the fractionation of the extract and the identification of the compounds. In-silico molecular docking of the AMPK alpha-2, beta and gamma subunits with the identified compounds was performed. Results Olive-tree leaves extract decreased the intracellular lipid accumulation through AMPK-dependent mechanisms in hypertrophic adipocytes. Secoiridoids, cinnamic acids, phenylethanoids and phenylpropanoids, flavonoids and lignans were the candidates predicted to account for this effect. Molecular docking revealed that some compounds may be AMPK-gamma modulators. The modulatory effects of compounds over the alpha and beta AMPK subunits appear to be less probable. Conclusions Olive-tree leaves polyphenols modulate AMPK activity, which may become a therapeutic aid in the management of obesity-associated disturbances. The natural occurrence of these compounds may have important nutritional implications for the design of functional ingredients. PMID:28278224

Insight into the Structural Determinants of Imidazole Scaffold-Based Derivatives as TNF-α Release Inhibitors by in Silico Explorations

PubMed Central

Wang, Yuan; Wu, Mingwei; Ai, Chunzhi; Wang, Yonghua

2015-01-01

Presently, 151 widely-diverse pyridinylimidazole-based compounds that show inhibitory activities at the TNF-α release were investigated. By using the distance comparison technique (DISCOtech), comparative molecular field analysis (CoMFA), and comparative molecular similarity index analysis (CoMSIA) methods, the pharmacophore models and the three-dimensional quantitative structure-activity relationships (3D-QSAR) of the compounds were explored. The proposed pharmacophore model, including two hydrophobic sites, two aromatic centers, two H-bond donor atoms, two H-bond acceptor atoms, and two H-bond donor sites characterizes the necessary structural features of TNF-α release inhibitors. Both the resultant CoMFA and CoMSIA models exhibited satisfactory predictability (with Q2 (cross-validated correlation coefficient) = 0.557, R2ncv (non-cross-validated correlation coefficient) = 0.740, R2pre (predicted correlation coefficient) = 0.749 and Q2 = 0.598, R2ncv = 0.767, R2pre = 0.860, respectively). Good consistency was observed between the 3D-QSAR models and the pharmacophore model that the hydrophobic interaction and hydrogen bonds play crucial roles in the mechanism of actions. The corresponding contour maps generated by these models provide more diverse information about the key intermolecular interactions of inhibitors with the surrounding environment. All these models have extended the understanding of imidazole-based compounds in the structure-activity relationship, and are useful for rational design and screening of novel 2-thioimidazole-based TNF-α release inhibitors. PMID:26307982

Insight into the Structural Determinants of Imidazole Scaffold-Based Derivatives as TNF-α Release Inhibitors by in Silico Explorations.

PubMed

Wang, Yuan; Wu, Mingwei; Ai, Chunzhi; Wang, Yonghua

2015-08-25

Presently, 151 widely-diverse pyridinylimidazole-based compounds that show inhibitory activities at the TNF-α release were investigated. By using the distance comparison technique (DISCOtech), comparative molecular field analysis (CoMFA), and comparative molecular similarity index analysis (CoMSIA) methods, the pharmacophore models and the three-dimensional quantitative structure-activity relationships (3D-QSAR) of the compounds were explored. The proposed pharmacophore model, including two hydrophobic sites, two aromatic centers, two H-bond donor atoms, two H-bond acceptor atoms, and two H-bond donor sites characterizes the necessary structural features of TNF-α release inhibitors. Both the resultant CoMFA and CoMSIA models exhibited satisfactory predictability (with Q(2) (cross-validated correlation coefficient) = 0.557, R(2)ncv (non-cross-validated correlation coefficient) = 0.740, R(2)pre (predicted correlation coefficient) = 0.749 and Q(2) = 0.598, R(2)ncv = 0.767, R(2)pre = 0.860, respectively). Good consistency was observed between the 3D-QSAR models and the pharmacophore model that the hydrophobic interaction and hydrogen bonds play crucial roles in the mechanism of actions. The corresponding contour maps generated by these models provide more diverse information about the key intermolecular interactions of inhibitors with the surrounding environment. All these models have extended the understanding of imidazole-based compounds in the structure-activity relationship, and are useful for rational design and screening of novel 2-thioimidazole-based TNF-α release inhibitors.

Reduced density gradient as a novel approach for estimating QSAR descriptors, and its application to 1, 4-dihydropyridine derivatives with potential antihypertensive effects.

PubMed

Jardínez, Christiaan; Vela, Alberto; Cruz-Borbolla, Julián; Alvarez-Mendez, Rodrigo J; Alvarado-Rodríguez, José G

2016-12-01

The relationship between the chemical structure and biological activity (log IC 50 ) of 40 derivatives of 1,4-dihydropyridines (DHPs) was studied using density functional theory (DFT) and multiple linear regression analysis methods. With the aim of improving the quantitative structure-activity relationship (QSAR) model, the reduced density gradient s( r) of the optimized equilibrium geometries was used as a descriptor to include weak non-covalent interactions. The QSAR model highlights the correlation between the log IC 50 with highest molecular orbital energy (E HOMO ), molecular volume (V), partition coefficient (log P), non-covalent interactions NCI(H4-G) and the dual descriptor [Δf(r)]. The model yielded values of R 2 =79.57 and Q 2 =69.67 that were validated with the next four internal analytical validations DK=0.076, DQ=-0.006, R P =0.056, and R N =0.000, and the external validation Q 2 boot =64.26. The QSAR model found can be used to estimate biological activity with high reliability in new compounds based on a DHP series. Graphical abstract The good correlation between the log IC 50 with the NCI (H4-G) estimated by the reduced density gradient approach of the DHP derivatives.

Multiple receptor conformation docking, dock pose clustering and 3D QSAR studies on human poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors.

PubMed

Fatima, Sabiha; Jatavath, Mohan Babu; Bathini, Raju; Sivan, Sree Kanth; Manga, Vijjulatha

2014-10-01

Poly(ADP-ribose) polymerase-1 (PARP-1) functions as a DNA damage sensor and signaling molecule. It plays a vital role in the repair of DNA strand breaks induced by radiation and chemotherapeutic drugs; inhibitors of this enzyme have the potential to improve cancer chemotherapy or radiotherapy. Three-dimensional quantitative structure activity relationship (3D QSAR) models were developed using comparative molecular field analysis, comparative molecular similarity indices analysis and docking studies. A set of 88 molecules were docked into the active site of six X-ray crystal structures of poly(ADP-ribose)polymerase-1 (PARP-1), by a procedure called multiple receptor conformation docking (MRCD), in order to improve the 3D QSAR models through the analysis of binding conformations. The docked poses were clustered to obtain the best receptor binding conformation. These dock poses from clustering were used for 3D QSAR analysis. Based on MRCD and QSAR information, some key features have been identified that explain the observed variance in the activity. Two receptor-based QSAR models were generated; these models showed good internal and external statistical reliability that is evident from the [Formula: see text], [Formula: see text] and [Formula: see text]. The identified key features enabled us to design new PARP-1 inhibitors.

TOPICAL REVIEW: Protein stability and enzyme activity at extreme biological temperatures

NASA Astrophysics Data System (ADS)

Feller, Georges

2010-08-01

Psychrophilic microorganisms thrive in permanently cold environments, even at subzero temperatures. To maintain metabolic rates compatible with sustained life, they have improved the dynamics of their protein structures, thereby enabling appropriate molecular motions required for biological activity at low temperatures. As a consequence of this structural flexibility, psychrophilic proteins are unstable and heat-labile. In the upper range of biological temperatures, thermophiles and hyperthermophiles grow at temperatures > 100 °C and synthesize ultra-stable proteins. However, thermophilic enzymes are nearly inactive at room temperature as a result of their compactness and rigidity. At the molecular level, both types of extremophilic proteins have adapted the same structural factors, but in opposite directions, to address either activity at low temperatures or stability in hot environments. A model based on folding funnels is proposed accounting for the stability-activity relationships in extremophilic proteins.

Molecular Modeling and Experimental Investigations of Nonlinear Optical Compounds Monosubstituted Derivatives of Dicyanovinylbenzene

NASA Technical Reports Server (NTRS)

Timofeeva, Tatiana V.; Nesterov, Vladimir N.; Antipin, Mikhail Yu.; Clark, Ronald D.; Sanghadasa, Mohan; Cardelino, Beatriz H.; Moore, Craig E.; Frazier, Donald O.

1999-01-01

A search for potential nonlinear optical compounds was performed using the Cambridge Structure Database and molecular modeling. We investigated a series of monosubstituted derivatives of dicyanovinylbenzene, since the nonlinear optical (NLO) properties of such derivatives (o-methoxy-dicyanovinylbenzene, DIVA) were studied earlier. The molecular geometry of these compounds was investigated with x-ray analysis and discussed along with the results of molecular mechanics and ab initio quantum chemical calculations. The influence of crystal packing on the planarity of the molecules of this series has been revealed. Two new compounds from the series studied, ortho-F and para-Cl-dicyanovinylbenzene, according to powder measurements, were found to be NLO compounds in the crystal state about 10 times more active than urea. The peculiarities of crystal structure formation in the framework of balance between van der Waals and electrostatic interactions have been discussed. The crystal shape of DIVA and two new NLO compounds have been calculated on the basis of the known crystal structure.

Identification of critical chemical features for Aurora kinase-B inhibitors using Hip-Hop, virtual screening and molecular docking

NASA Astrophysics Data System (ADS)

Sakkiah, Sugunadevi; Thangapandian, Sundarapandian; John, Shalini; Lee, Keun Woo

2011-01-01

This study was performed to find the selective chemical features for Aurora kinase-B inhibitors using the potent methods like Hip-Hop, virtual screening, homology modeling, molecular dynamics and docking. The best hypothesis, Hypo1 was validated toward a wide range of test set containing the selective inhibitors of Aurora kinase-B. Homology modeling and molecular dynamics studies were carried out to perform the molecular docking studies. The best hypothesis Hypo1 was used as a 3D query to screen the chemical databases. The screened molecules from the databases were sorted based on ADME and drug like properties. The selective hit compounds were docked and the hydrogen bond interactions with the critical amino acids present in Aurora kinase-B were compared with the chemical features present in the Hypo1. Finally, we suggest that the chemical features present in the Hypo1 are vital for a molecule to inhibit the Aurora kinase-B activity.

Dynamic properties of molecular motors in burnt-bridge models

NASA Astrophysics Data System (ADS)

Artyomov, Maxim N.; Morozov, Alexander Yu; Pronina, Ekaterina; Kolomeisky, Anatoly B.

2007-08-01

Dynamic properties of molecular motors that fuel their motion by actively interacting with underlying molecular tracks are studied theoretically via discrete-state stochastic 'burnt-bridge' models. The transport of the particles is viewed as an effective diffusion along one-dimensional lattices with periodically distributed weak links. When an unbiased random walker passes the weak link it can be destroyed ('burned') with probability p, providing a bias in the motion of the molecular motor. We present a theoretical approach that allows one to calculate exactly all dynamic properties of motor proteins, such as velocity and dispersion, under general conditions. It is found that dispersion is a decreasing function of the concentration of bridges, while the dependence of dispersion on the burning probability is more complex. Our calculations also show a gap in dispersion for very low concentrations of weak links or for very low burning probabilities which indicates a dynamic phase transition between unbiased and biased diffusion regimes. Theoretical findings are supported by Monte Carlo computer simulations.

Docking Based 3D-QSAR Study of Tricyclic Guanidine Analogues of Batzelladine K as anti-malarial agents

NASA Astrophysics Data System (ADS)

Ahmed, Nafees; Anwar, Sirajudheen; Thet Htar, Thet

2017-06-01

The Plasmodium falciparum Lactate Dehydrogenase enzyme (PfLDH) catalyzes inter-conversion of pyruvate to lactate during glycolysis producing the energy required for parasitic growth. The PfLDH has been studied as a potential molecular target for development of anti-malarial agents. In an attempt to find the potent inhibitor of PfLDH, we have used Discovery studio to perform molecular docking in the active binding pocket of PfLDH by CDOCKER, followed by three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of tricyclic guanidine batzelladine compounds, which were previously synthesized in our laboratory. Docking studies showed that there is a very strong correlation between in silico and in vitro results. Based on docking results, a highly predictive 3D-QSAR model was developed with q2 of 0.516. The model has predicted r2 of 0.91 showing that predicted IC50 values are in good agreement with experimental IC50 values. The results obtained from this study revealed the developed model can be used to design new anti-malarial compounds based on tricyclic guanidine derivatives and to predict activities of new inhibitors.

Docking Based 3D-QSAR Study of Tricyclic Guanidine Analogues of Batzelladine K As Anti-Malarial Agents.

PubMed

Ahmed, Nafees; Anwar, Sirajudheen; Thet Htar, Thet

2017-01-01

The Plasmodium falciparum Lactate Dehydrogenase enzyme ( Pf LDH) catalyzes inter-conversion of pyruvate to lactate during glycolysis producing the energy required for parasitic growth. The Pf LDH has been studied as a potential molecular target for development of anti-malarial agents. In an attempt to find the potent inhibitor of Pf LDH, we have used Discovery studio to perform molecular docking in the active binding pocket of Pf LDH by CDOCKER, followed by three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of tricyclic guanidine batzelladine compounds, which were previously synthesized in our laboratory. Docking studies showed that there is a very strong correlation between in silico and in vitro results. Based on docking results, a highly predictive 3D-QSAR model was developed with q 2 of 0.516. The model has predicted r 2 of 0.91 showing that predicted IC 50 values are in good agreement with experimental IC 50 values. The results obtained from this study revealed the developed model can be used to design new anti-malarial compounds based on tricyclic guanidine derivatives and to predict activities of new inhibitors.

Docking Based 3D-QSAR Study of Tricyclic Guanidine Analogues of Batzelladine K As Anti-Malarial Agents

PubMed Central

Ahmed, Nafees; Anwar, Sirajudheen; Thet Htar, Thet

2017-01-01

The Plasmodium falciparum Lactate Dehydrogenase enzyme (PfLDH) catalyzes inter-conversion of pyruvate to lactate during glycolysis producing the energy required for parasitic growth. The PfLDH has been studied as a potential molecular target for development of anti-malarial agents. In an attempt to find the potent inhibitor of PfLDH, we have used Discovery studio to perform molecular docking in the active binding pocket of PfLDH by CDOCKER, followed by three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of tricyclic guanidine batzelladine compounds, which were previously synthesized in our laboratory. Docking studies showed that there is a very strong correlation between in silico and in vitro results. Based on docking results, a highly predictive 3D-QSAR model was developed with q2 of 0.516. The model has predicted r2 of 0.91 showing that predicted IC50 values are in good agreement with experimental IC50 values. The results obtained from this study revealed the developed model can be used to design new anti-malarial compounds based on tricyclic guanidine derivatives and to predict activities of new inhibitors. PMID:28664157

Molecular friction dissipation and mode coupling in organic monolayers and polymer films.

PubMed

Knorr, Daniel B; Widjaja, Peggy; Acton, Orb; Overney, René M

2011-03-14

The impact of thermally active molecular rotational and translational relaxation modes on the friction dissipation process involving smooth nano-asperity contacts has been studied by atomic force microscopy, using the widely known Eyring analysis and a recently introduced method, dubbed intrinsic friction analysis. Two distinctly different model systems, i.e., monolayers of octadecyl-phosphonic acid (ODPA) and thin films of poly(tert-butyl acrylate) (PtBA) were investigated regarding shear-rate critical dissipation phenomena originating from diverging mode coupling behaviors between the external shear perturbation and the internal molecular modes of relaxation. Rapidly (ODPA) versus slowly (PtBA) relaxing systems, in comparison to the sliding rate, revealed monotonous logarithmic and nonmonotonous spectral shear rate dependences, respectively. Shear coupled, enthalpic activation energies of 46 kJ∕mol for ODPA and of 35 and ∼65 kJ∕mol for PtBA (below and above the glass transition) were found that could be attributed to intrinsic modes of relaxations. Also, entropic energies involved in the cooperative backbone mobility of PtBA could be quantified, dwarfing the activation energy by more than a factor of five. This study provides (i) a material specific understanding of the molecular scale dissipation process in shear compliant substances, (ii) analyses of material intrinsic shear-rate mode coupling, shear coordination and energetics, (iii) a verification of Eyring's model applied to tribological systems toward material intrinsic specificity, and (iv) a valuable extension of the Eyring analysis for complex macromolecular systems that are slowly relaxing, and thus, exhibit shear-rate mode coupling.

Molecular Phenotyping Combines Molecular Information, Biological Relevance, and Patient Data to Improve Productivity of Early Drug Discovery.

PubMed

Drawnel, Faye Marie; Zhang, Jitao David; Küng, Erich; Aoyama, Natsuyo; Benmansour, Fethallah; Araujo Del Rosario, Andrea; Jensen Zoffmann, Sannah; Delobel, Frédéric; Prummer, Michael; Weibel, Franziska; Carlson, Coby; Anson, Blake; Iacone, Roberto; Certa, Ulrich; Singer, Thomas; Ebeling, Martin; Prunotto, Marco

2017-05-18

Today, novel therapeutics are identified in an environment which is intrinsically different from the clinical context in which they are ultimately evaluated. Using molecular phenotyping and an in vitro model of diabetic cardiomyopathy, we show that by quantifying pathway reporter gene expression, molecular phenotyping can cluster compounds based on pathway profiles and dissect associations between pathway activities and disease phenotypes simultaneously. Molecular phenotyping was applicable to compounds with a range of binding specificities and triaged false positives derived from high-content screening assays. The technique identified a class of calcium-signaling modulators that can reverse disease-regulated pathways and phenotypes, which was validated by structurally distinct compounds of relevant classes. Our results advocate for application of molecular phenotyping in early drug discovery, promoting biological relevance as a key selection criterion early in the drug development cascade. Copyright © 2017 Elsevier Ltd. All rights reserved.

Molecular Modeling in Drug Design for the Development of Organophosphorus Antidotes/Prophylactics.

DTIC Science & Technology

1986-06-01

multidimensional statistical QSAR analysis techniques to suggest new structures for synthesis and evaluation. C. Application of quantum chemical techniques to...compounds for synthesis and testing for antidotal potency. E. Use of computer-assisted methods to determine the steric constraints at the active site...modeling techniques to model the enzyme acetylcholinester-se. H. Suggestion of some novel compounds for synthesis and testing for reactivating

3D QSAR based design of novel oxindole derivative as 5HT7 inhibitors.

PubMed

Chitta, Aparna; Sivan, Sree Kanth; Manga, Vijjulatha

2014-06-01

To understand the structural requirements of 5-hydroxytryptamine (5HT7) receptor inhibitors and to design new ligands against 5HT7 receptor with enhanced inhibitory potency, a three-dimensional quantitative structure-activity relationship study with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) for a data set of 56 molecules consisting of oxindole, tetrahydronaphthalene, aryl ketone substituted arylpiperazinealkylamide derivatives was performed. Derived model showed good statistical reliability in terms of predicting 5HT7 inhibitory activity of the molecules, based on molecular property fields like steric, electrostatic, hydrophobic, hydrogen bond donor and hydrogen bond acceptor fields. This is evident from statistical parameters like conventional r2 and a cross validated (q2) values of 0.985, 0.743 for CoMFA and 0.970, 0.608 for CoMSIA, respectively. Predictive ability of the models to determine 5HT7 antagonistic activity is validated using a test set of 16 molecules that were not included in the training set. Predictive r2 obtained for the test set was 0.560 and 0.619 for CoMFA and CoMSIA, respectively. Steric, electrostatic fields majorly contributed toward activity which forms the basis for design of new molecules. Absorption, distribution, metabolism and elimination (ADME) calculation using QikProp 2.5 (Schrodinger 2010, Portland, OR) reveals that the molecules confer to Lipinski's rule of five in majority of the cases.

Redox biotransformation and delivery of anthracycline anticancer antibiotics: How interpretable structure-activity relationships of lethality using electrophilicity and the London formula for dispersion interaction work.

PubMed

Pang, Siu-Kwong

2017-03-30

Quantum chemical methods and molecular mechanics approaches face a lot of challenges in drug metabolism study because of their either insufficient accuracy or huge computational cost, or lack of clear molecular level pictures for building computational models. Low-cost QSAR methods can often be carried out even though molecular level pictures are not well defined; however, they show difficulty in identifying the mechanisms of drug metabolism and delineating the effects of chemical structures on drug toxicity because a certain amount of molecular descriptors are difficult to be interpreted. In order to make a breakthrough, it was proposed that mechanistically interpretable molecular descriptors were used to correlate with biological activity to establish structure-activity plots. The mechanistically interpretable molecular descriptors used in this study include electrophilicity and the mathematical function in the London formula for dispersion interaction, and they were calculated using quantum chemical methods. The biological activity is the lethality of anthracycline anticancer antibiotics denoted as log LD50, which were obtained by intraperitoneal injection into mice. The results reveal that the plots for electrophilicity, which can be interpreted as redox reactivity of anthracyclines, can describe oxidative degradation for detoxification and reductive bioactivation for toxicity induction. The plots for the dispersion interaction function, which represent the attraction between anthracyclines and biomolecules, can describe efflux from and influx into target cells of toxicity. The plots can also identify three structural scaffolds of anthracyclines that have different metabolic pathways, resulting in their different toxicity behavior. This structure-dependent toxicity behavior revealed in the plots can provide perspectives on design of anthracycline anticancer antibiotics. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

C. elegans model of neuronal aging

PubMed Central

Peng, Chiu-Ying; Chen, Chun-Hao; Hsu, Jiun-Min

2011-01-01

Aging of the nervous system underlies the behavioral and cognitive decline associated with senescence. Understanding the molecular and cellular basis of neuronal aging will therefore contribute to the development of effective treatments for aging and age-associated neurodegenerative disorders. Despite this pressing need, there are surprisingly few animal models that aim at recapitulating neuronal aging in a physiological context. We recently developed a C. elegans model of neuronal aging, and showed that age-dependent neuronal defects are regulated by insulin signaling. We identified electrical activity and epithelial attachment as two critical factors in the maintenance of structural integrity of C. elegans touch receptor neurons. These findings open a new avenue for elucidating the molecular mechanisms that maintain neuronal structures during the course of aging. PMID:22446530

Use of the Monte Carlo Method for OECD Principles-Guided QSAR Modeling of SIRT1 Inhibitors.

PubMed

Kumar, Ashwani; Chauhan, Shilpi

2017-01-01

SIRT1 inhibitors offer therapeutic potential for the treatment of a number of diseases including cancer and human immunodeficiency virus infection. A diverse series of 45 compounds with reported SIRT1 inhibitory activity has been employed for the development of quantitative structure-activity relationship (QSAR) models using the Monte Carlo optimization method. This method makes use of simplified molecular input line entry system notation of the molecular structure. The QSAR models were built up according to OECD principles. Three subsets of three splits were examined and validated by respective external sets. All the three described models have good statistical quality. The best model has the following statistical characteristics: R 2  = 0.8350, Q 2 test  = 0.7491 for the test set and R 2  = 0.9655, Q 2 ext  = 0.9261 for the validation set. In the mechanistic interpretation, structural attributes responsible for the endpoint increase and decrease are defined. Further, the design of some prospective SIRT1 inhibitors is also presented on the basis of these structural attributes. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

QSAR models to predict mutagenicity of acrylates, methacrylates and alpha,beta-unsaturated carbonyl compounds.

PubMed

Pérez-Garrido, Alfonso; Helguera, Aliuska Morales; Rodríguez, Francisco Girón; Cordeiro, M Natália D S

2010-05-01

The purpose of this study is to develop a quantitative structure-activity relationship (QSAR) model that can distinguish mutagenic from non-mutagenic species with alpha,beta-unsaturated carbonyl moiety using two endpoints for this activity - Ames test and mammalian cell gene mutation test - and also to gather information about the molecular features that most contribute to eliminate the mutagenic effects of these chemicals. Two data sets were used for modeling the two mutagenicity endpoints: (1) Ames test and (2) mammalian cells mutagenesis. The first one comprised 220 molecules, while the second one 48 substances, ranging from acrylates, methacrylates to alpha,beta-unsaturated carbonyl compounds. The QSAR models were developed by applying linear discriminant analysis (LDA) along with different sets of descriptors computed using the DRAGON software. For both endpoints, there was a concordance of 89% in the prediction and 97% confidentiality by combining the three models for the Ames test mutagenicity. We have also identified several structural alerts to assist the design of new monomers. These individual models and especially their combination are attractive from the point of view of molecular modeling and could be used for the prediction and design of new monomers that do not pose a human health risk. 2010 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

Theoretical study on interaction of cytochrome f and plastocyanin complex by a simple coarse-grained model with molecular crowding effect

NASA Astrophysics Data System (ADS)

Nakagawa, Satoshi; Kurniawan, Isman; Kodama, Koichi; Arwansyah, Muhammad Saleh; Kawaguchi, Kazutomo; Nagao, Hidemi

2018-03-01

We present a simple coarse-grained model with the molecular crowding effect in solvent to investigate the structure and dynamics of protein complexes including association and/or dissociation processes and investigate some physical properties such as the structure and the reaction rate from the viewpoint of the hydrophobic intermolecular interactions of protein complex. In the present coarse-grained model, a function depending upon the density of hydrophobic amino acid residues in a binding area of the complex is introduced, and the function involves the molecular crowding effect for the intermolecular interactions of hydrophobic amino acid residues between proteins. We propose a hydrophobic intermolecular potential energy between proteins by using the density-dependent function. The present coarse-grained model is applied to the complex of cytochrome f and plastocyanin by using the Langevin dynamics simulation to investigate some physical properties such as the complex structure, the electron transfer reaction rate constant from plastocyanin to cytochrome f and so on. We find that for proceeding the electron transfer reaction, the distance between metals in their active sites is necessary within about 18 Å. We discuss some typical complex structures formed in the present simulation in relation to the molecular crowding effect on hydrophobic interactions.

Application of the thermorheologically complex nonlinear Adam-Gibbs model for the glass transition to molecular motion in hydrated proteins.

PubMed

Hodge, Ian M

2006-08-01

The nonlinear thermorheologically complex Adam Gibbs (extended "Scherer-Hodge") model for the glass transition is applied to enthalpy relaxation data reported by Sartor, Mayer, and Johari for hydrated methemoglobin. A sensible range in values for the average localized activation energy is obtained (100-200 kJ mol(-1)). The standard deviation in the inferred Gaussian distribution of activation energies, computed from the reported KWW beta-parameter, is approximately 30% of the average, consistent with the suggestion that some relaxation processes in hydrated proteins have exceptionally low activation energies.

Prediction of luciferase inhibitors by the high-performance MIEC-GBDT approach based on interaction energetic patterns.

PubMed

Chen, Fu; Sun, Huiyong; Liu, Hui; Li, Dan; Li, Youyong; Hou, Tingjun

2017-04-12

High-throughput screening (HTS) is widely applied in many fields ranging from drug discovery to clinical diagnostics and toxicity assessment. Firefly luciferase is commonly used as a reporter to monitor the effect of chemical compounds on the activity of a specific target or pathway in HTS. However, the false positive rate of luciferase-based HTS is relatively high because many artifacts or promiscuous compounds that have direct interaction with the luciferase reporter enzyme are usually identified as active compounds (hits). Therefore, it is necessary to develop a rapid screening method to identify these compounds that can inhibit the luciferase activity directly. In this study, a virtual screening (VS) classification model called MIEC-GBDT (MIEC: Molecular Interaction Energy Components; GBDT: Gradient Boosting Decision Tree) was developed to distinguish luciferase inhibitors from non-inhibitors. The MIECs calculated by Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) free energy decomposition were used to energetically characterize the binding pattern of each small molecule at the active site of luciferase, and then the GBDT algorithm was employed to construct the classifiers based on MIECs. The predictions to the test set show that the optimized MIEC-GBDT model outperformed molecular docking and MM/GBSA rescoring. The best MIEC-GBDT model based on the MIECs with the energy terms of ΔG ele , ΔG vdW , ΔG GB , and ΔG SA achieves the prediction accuracies of 87.2% and 90.3% for the inhibitors and non-inhibitors in the test sets, respectively. Moreover, the energetic analysis of the vital residues suggests that the energetic contributions of the vital residues to the binding of inhibitors are quite different from those to the binding of non-inhibitors. These results suggest that the MIEC-GBDT model is reliable and can be used as a powerful tool to identify potential interference compounds in luciferase-based HTS experiments.

Simulated binding of transcription factors to active and inactive regions folds human chromosomes into loops, rosettes and topological domains

PubMed Central

Brackley, Chris A.; Johnson, James; Kelly, Steven; Cook, Peter R.; Marenduzzo, Davide

2016-01-01

Biophysicists are modeling conformations of interphase chromosomes, often basing the strengths of interactions between segments distant on the genetic map on contact frequencies determined experimentally. Here, instead, we develop a fitting-free, minimal model: bivalent or multivalent red and green ‘transcription factors’ bind to cognate sites in strings of beads (‘chromatin’) to form molecular bridges stabilizing loops. In the absence of additional explicit forces, molecular dynamic simulations reveal that bound factors spontaneously cluster—red with red, green with green, but rarely red with green—to give structures reminiscent of transcription factories. Binding of just two transcription factors (or proteins) to active and inactive regions of human chromosomes yields rosettes, topological domains and contact maps much like those seen experimentally. This emergent ‘bridging-induced attraction’ proves to be a robust, simple and generic force able to organize interphase chromosomes at all scales. PMID:27060145

3D-Pharmacophore Identification for κ-Opioid Agonists Using Ligand-Based Drug-Design Techniques

NASA Astrophysics Data System (ADS)

Yamaotsu, Noriyuki; Hirono, Shuichi

A selective κ-opioid receptor (KOR) agonist might act as a powerful analgesic without the side effects of μ-opioid receptor-selective drugs such as morphine. The eight classes of known KOR agonists have different chemical structures, making it difficult to construct a pharmacophore model that takes them all into account. Here, we summarize previous efforts to identify the pharmacophore for κ-opioid agonists and propose a new three-dimensional pharmacophore model that encompasses the κ-activities of all classes. This utilizes conformational sampling of agonists by high-temperature molecular dynamics and pharmacophore extraction through a series of molecular superpositions.

Ab initio quantum chemical study of electron transfer in carboranes

NASA Astrophysics Data System (ADS)

Pati, Ranjit; Pineda, Andrew C.; Pandey, Ravindra; Karna, Shashi P.

2005-05-01

The electron transfer (ET) properties of 10- and 12-vertex carboranes are investigated by the ab initio Hartree-Fock method within the Marcus-Hush (MH) two-state model and the Koopman theorem (KT) approach. The calculated value of the ET coupling matrix element, VAB, is consistently higher in the KT approach than in the MH two-state model. For the carborane molecules functionalized by -CH 2 groups at C-vertices, VAB strongly depends on the relative orientation of the planes containing the terminal -CH 2 groups. The predicted conformation dependence of VAB offers a molecular mechanism to control ET between two active centers in molecular systems.

Pharmacophore modeling, virtual screening and molecular docking of ATPase inhibitors of HSP70.

PubMed

Sangeetha, K; Sasikala, R P; Meena, K S

2017-10-01

Heat shock protein 70 is an effective anticancer target as it influences many signaling pathways. Hence the study investigated the important pharmacophore feature required for ATPase inhibitors of HSP70 by generating a ligand based pharmacophore model followed by virtual based screening and subsequent validation by molecular docking in Discovery studio V4.0. The most extrapolative pharmacophore model (hypotheses 8) consisted of four hydrogen bond acceptors. Further validation by external test set prediction identified 200 hits from Mini Maybridge, Drug Diverse, SCPDB compounds and Phytochemicals. Consequently, the screened compounds were refined by rule of five, ADMET and molecular docking to retain the best competitive hits. Finally Phytochemical compounds Muricatetrocin B, Diacetylphiladelphicalactone C, Eleutheroside B and 5-(3-{[1-(benzylsulfonyl)piperidin-4-yl]amino}phenyl)- 4-bromo-3-(carboxymethoxy)thiophene-2-carboxylic acid were obtained as leads to inhibit the ATPase activity of HSP70 in our findings and thus can be proposed for further in vitro and in vivo evaluation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Building up a QSAR model for toxicity toward Tetrahymena pyriformis by the Monte Carlo method: A case of benzene derivatives.

PubMed

Toropova, Alla P; Schultz, Terry W; Toropov, Andrey A

2016-03-01

Data on toxicity toward Tetrahymena pyriformis is indicator of applicability of a substance in ecologic and pharmaceutical aspects. Quantitative structure-activity relationships (QSARs) between the molecular structure of benzene derivatives and toxicity toward T. pyriformis (expressed as the negative logarithms of the population growth inhibition dose, mmol/L) are established. The available data were randomly distributed three times into the visible training and calibration sets, and invisible validation sets. The statistical characteristics for the validation set are the following: r(2)=0.8179 and s=0.338 (first distribution); r(2)=0.8682 and s=0.341 (second distribution); r(2)=0.8435 and s=0.323 (third distribution). These models are built up using only information on the molecular structure: no data on physicochemical parameters, 3D features of the molecular structure and quantum mechanics descriptors are involved in the modeling process. Copyright © 2016 Elsevier B.V. All rights reserved.

Computing by physical interaction in neurons.

PubMed

Aur, Dorian; Jog, Mandar; Poznanski, Roman R

2011-12-01

The electrodynamics of action potentials represents the fundamental level where information is integrated and processed in neurons. The Hodgkin-Huxley model cannot explain the non-stereotyped spatial charge density dynamics that occur during action potential propagation. Revealed in experiments as spike directivity, the non-uniform charge density dynamics within neurons carry meaningful information and suggest that fragments of information regarding our memories are endogenously stored in structural patterns at a molecular level and are revealed only during spiking activity. The main conceptual idea is that under the influence of electric fields, efficient computation by interaction occurs between charge densities embedded within molecular structures and the transient developed flow of electrical charges. This process of computation underlying electrical interactions and molecular mechanisms at the subcellular level is dissimilar from spiking neuron models that are completely devoid of physical interactions. Computation by interaction describes a more powerful continuous model of computation than the one that consists of discrete steps as represented in Turing machines.

Modeling of lipase catalyzed ring-opening polymerization of epsilon-caprolactone.

PubMed

Sivalingam, G; Madras, Giridhar

2004-01-01

Enzymatic ring-opening polymerization of epsilon-caprolactone by various lipases was investigated in toluene at various temperatures. The determination of molecular weight and structural identification was carried out with gel permeation chromatography and proton NMR, respectively. Among the various lipases employed, an immobilized lipase from Candida antartica B (Novozym 435) showed the highest catalytic activity. The polymerization of epsilon-caprolactone by Novozym 435 showed an optimal temperature of 65 degrees C and an optimum toluene content of 50/50 v/v of toluene and epsilon-caprolactone. As lipases can degrade polyesters, a maximum in the molecular weight with time was obtained due to the competition of ring opening polymerization and degradation by specific chain end scission. The optimum temperature, toluene content, and the variation of molecular weight with time are consistent with earlier observations. A comprehensive model based on continuous distribution kinetics was developed to model these phenomena. The model accounts for simultaneous polymerization, degradation and enzyme deactivation and provides a technique to determine the rate coefficients for these processes. The dependence of these rate coefficients with temperature and monomer concentration is also discussed.

Charge transfer in model peptides: obtaining Marcus parameters from molecular simulation.

PubMed

Heck, Alexander; Woiczikowski, P Benjamin; Kubař, Tomáš; Giese, Bernd; Elstner, Marcus; Steinbrecher, Thomas B

2012-02-23

Charge transfer within and between biomolecules remains a highly active field of biophysics. Due to the complexities of real systems, model compounds are a useful alternative to study the mechanistic fundamentals of charge transfer. In recent years, such model experiments have been underpinned by molecular simulation methods as well. In this work, we study electron hole transfer in helical model peptides by means of molecular dynamics simulations. A theoretical framework to extract Marcus parameters of charge transfer from simulations is presented. We find that the peptides form stable helical structures with sequence dependent small deviations from ideal PPII helices. We identify direct exposure of charged side chains to solvent as a cause of high reorganization energies, significantly larger than typical for electron transfer in proteins. This, together with small direct couplings, makes long-range superexchange electron transport in this system very slow. In good agreement with experiment, direct transfer between the terminal amino acid side chains can be dicounted in favor of a two-step hopping process if appropriate bridging groups exist. © 2012 American Chemical Society

Modeling Natural Anti-Inflammatory Compounds by Molecular Topology

PubMed Central

Galvez-Llompart, María; Zanni, Riccardo; García-Domenech, Ramón

2011-01-01

One of the main pharmacological problems today in the treatment of chronic inflammation diseases consists of the fact that anti-inflammatory drugs usually exhibit side effects. The natural products offer a great hope in the identification of bioactive lead compounds and their development into drugs for treating inflammatory diseases. Computer-aided drug design has proved to be a very useful tool for discovering new drugs and, specifically, Molecular Topology has become a good technique for such a goal. A topological-mathematical model, obtained by linear discriminant analysis, has been developed for the search of new anti-inflammatory natural compounds. An external validation obtained with the remaining compounds (those not used in building up the model), has been carried out. Finally, a virtual screening on natural products was performed and 74 compounds showed actual anti-inflammatory activity. From them, 54 had been previously described as anti-inflammatory in the literature. This can be seen as a plus in the model validation and as a reinforcement of the role of Molecular Topology as an efficient tool for the discovery of new anti-inflammatory natural compounds. PMID:22272145

Bifunctional homodimeric triokinase/FMN cyclase: contribution of protein domains to the activities of the human enzyme and molecular dynamics simulation of domain movements.

PubMed

Rodrigues, Joaquim Rui; Couto, Ana; Cabezas, Alicia; Pinto, Rosa María; Ribeiro, João Meireles; Canales, José; Costas, María Jesús; Cameselle, José Carlos

2014-04-11

Mammalian triokinase, which phosphorylates exogenous dihydroxyacetone and fructose-derived glyceraldehyde, is neither molecularly identified nor firmly associated to an encoding gene. Human FMN cyclase, which splits FAD and other ribonucleoside diphosphate-X compounds to ribonucleoside monophosphate and cyclic X-phosphodiester, is identical to a DAK-encoded dihydroxyacetone kinase. This bifunctional protein was identified as triokinase. It was modeled as a homodimer of two-domain (K and L) subunits. Active centers lie between K1 and L2 or K2 and L1: dihydroxyacetone binds K and ATP binds L in different subunits too distant (≈ 14 Å) for phosphoryl transfer. FAD docked to the ATP site with ribityl 4'-OH in a possible near-attack conformation for cyclase activity. Reciprocal inhibition between kinase and cyclase reactants confirmed substrate site locations. The differential roles of protein domains were supported by their individual expression: K was inactive, and L displayed cyclase but not kinase activity. The importance of domain mobility for the kinase activity of dimeric triokinase was highlighted by molecular dynamics simulations: ATP approached dihydroxyacetone at distances below 5 Å in near-attack conformation. Based upon structure, docking, and molecular dynamics simulations, relevant residues were mutated to alanine, and kcat and Km were assayed whenever kinase and/or cyclase activity was conserved. The results supported the roles of Thr(112) (hydrogen bonding of ATP adenine to K in the closed active center), His(221) (covalent anchoring of dihydroxyacetone to K), Asp(401) and Asp(403) (metal coordination to L), and Asp(556) (hydrogen bonding of ATP or FAD ribose to L domain). Interestingly, the His(221) point mutant acted specifically as a cyclase without kinase activity.

A Systems Biology Approach to the Coordination of Defensive and Offensive Molecular Mechanisms in the Innate and Adaptive Host–Pathogen Interaction Networks

PubMed Central

Wu, Chia-Chou; Chen, Bor-Sen

2016-01-01

Infected zebrafish coordinates defensive and offensive molecular mechanisms in response to Candida albicans infections, and invasive C. albicans coordinates corresponding molecular mechanisms to interact with the host. However, knowledge of the ensuing infection-activated signaling networks in both host and pathogen and their interspecific crosstalk during the innate and adaptive phases of the infection processes remains incomplete. In the present study, dynamic network modeling, protein interaction databases, and dual transcriptome data from zebrafish and C. albicans during infection were used to infer infection-activated host–pathogen dynamic interaction networks. The consideration of host–pathogen dynamic interaction systems as innate and adaptive loops and subsequent comparisons of inferred innate and adaptive networks indicated previously unrecognized crosstalk between known pathways and suggested roles of immunological memory in the coordination of host defensive and offensive molecular mechanisms to achieve specific and powerful defense against pathogens. Moreover, pathogens enhance intraspecific crosstalk and abrogate host apoptosis to accommodate enhanced host defense mechanisms during the adaptive phase. Accordingly, links between physiological phenomena and changes in the coordination of defensive and offensive molecular mechanisms highlight the importance of host–pathogen molecular interaction networks, and consequent inferences of the host–pathogen relationship could be translated into biomedical applications. PMID:26881892

A Systems Biology Approach to the Coordination of Defensive and Offensive Molecular Mechanisms in the Innate and Adaptive Host-Pathogen Interaction Networks.

PubMed

Wu, Chia-Chou; Chen, Bor-Sen

2016-01-01

Infected zebrafish coordinates defensive and offensive molecular mechanisms in response to Candida albicans infections, and invasive C. albicans coordinates corresponding molecular mechanisms to interact with the host. However, knowledge of the ensuing infection-activated signaling networks in both host and pathogen and their interspecific crosstalk during the innate and adaptive phases of the infection processes remains incomplete. In the present study, dynamic network modeling, protein interaction databases, and dual transcriptome data from zebrafish and C. albicans during infection were used to infer infection-activated host-pathogen dynamic interaction networks. The consideration of host-pathogen dynamic interaction systems as innate and adaptive loops and subsequent comparisons of inferred innate and adaptive networks indicated previously unrecognized crosstalk between known pathways and suggested roles of immunological memory in the coordination of host defensive and offensive molecular mechanisms to achieve specific and powerful defense against pathogens. Moreover, pathogens enhance intraspecific crosstalk and abrogate host apoptosis to accommodate enhanced host defense mechanisms during the adaptive phase. Accordingly, links between physiological phenomena and changes in the coordination of defensive and offensive molecular mechanisms highlight the importance of host-pathogen molecular interaction networks, and consequent inferences of the host-pathogen relationship could be translated into biomedical applications.

Modeling molecular hydrogen emission in M dwarf exoplanetary systems

NASA Astrophysics Data System (ADS)

Evonosky, William; France, Kevin; Kruczek, Nick E.; Youngblood, Allison; Measurements of the Ultraviolet Spectral Characteristics of Low-mass Exoplanet host Stars (MUSCLES)

2017-01-01

Exoplanets orbiting low-mass stars are prime candidates for atmospheric characterization due to their astronomical abundance and short orbital periods. These planets orbit stars that are often more active than main sequence solar-type stars. They are exposed to differing levels of ultraviolet radiation which can cause traditional “biosignature” gases to be generated abiotically, potentially causing false-positive identifications of life. We modeled the recently discovered molecular hydrogen emission in the ultraviolet spectra (1350 - 1650 Å) as arising from the stellar surface, excited by radiation generated in the upper chromosphere. The model was compared with observed hydrogen emission from the “Measurements of the Ultraviolet Spectral Characteristics of Low-mass Exoplanet host Stars” (MUSCLES) survey by conducting a grid search and implementing a chi-squared minimization routine. We considered only progressions from the [1, 4] and [1, 7] first excited electronic levels. Our modeling procedure varied the atomic hydrogen column density (in the chromosphere) as well as the photospheric molecular hydrogen column density and temperature. The model required as an input a reconstructed intrinsic Lyman α profile which served as the pumping radiation for the molecular hydrogen. We found that an atomic hydrogen column density of log10N(H I) = 14.13 ± 0.16 cm-2 represents a breaking point above which there is not enough Lyman α flux available to excite a significant molecular hydrogen population into the [1, 7] state. We also present H2 temperatures which may suggest that star spots on low mass stars persist longer, and encompass more area than star spots on solar-type stars.