Structure-activity relationship and docking studies of thiazolidinedione-type compounds with monoamine oxidase B.

PubMed

Carroll, Richard T; Dluzen, Dean E; Stinnett, Hilary; Awale, Prabha S; Funk, Max O; Geldenhuys, Werner J

2011-08-15

The neuroprotective activity of pioglitazone and rosiglitazone in the MPTP parkinsonian mouse prompted us to evaluate a set of thiazolidinedione (TZD) type compounds for monoamine oxidase A and B inhibition activity. These compounds were able to inhibit MAO-B over several log units of magnitude (82 nM to 600 μM). Initial structure-activity relationship studies identified key areas to modify the aromatic substituted TZD compounds. Primarily, substitutions on the aromatic group and the TZD nitrogen were key areas where activity was enhanced within this group of compounds. Copyright © 2011 Elsevier Ltd. All rights reserved.

Ecological Structure Activity Relationships

EPA Science Inventory

Ecological Structure Activity Relationships, v1.00a, February 2009
ECOSAR (Ecological Structure Activity Relationships) is a personal computer software program that is used to estimate the toxicity of chemicals used in industry and discharged into water. The program predicts...

Synthesis, fungicidal activity, structure-activity relationships (SARs) and density functional theory (DFT) studies of novel strobilurin analogues containing arylpyrazole rings.

PubMed

Liu, Yuanyuan; Lv, Kunzhi; Li, Yi; Nan, Qiuli; Xu, Jinyuan

2018-05-18

A series of novel strobilurin analogues (1a-1f, 2a-2e, 3a-3e) containing arylpyrazole rings were synthesized and characterized by NMR spectroscopy. The structures of 1f, 2b and 3b were also determined by single crystal X-ray diffraction analysis. These analogues were collected together with other twenty-eight similar compounds 4a-4f, 5a-5h, 6a-6h and 7a-7f from our previous studies, for in vitro bioassays and thorough structure-activity relationships (SARs) studies. Most compounds exhibited excellent-to-good fungicidal activity against Rhizoctonia solani, especially 5c, 7a, 6c, and 3b with 98.94%, 83.40%, 71.40% and 65.87% inhibition rates at 0.1 μg mL -1 , respectively, better than commercial pyraclostrobin. Comparative molecular field analysis (CoMFA) was employed to study three-dimensional quantitative structure-activity relationships (3D-QSARs). Density functional theory (DFT) calculation was also carried out to provide more information regarding SARs. The present work provided some hints for developing novel strobilurin fungicides.

Ring-substituted 4-hydroxy-1H-quinolin-2-ones: preparation and biological activity.

PubMed

Jampilek, Josef; Musiol, Robert; Pesko, Matus; Kralova, Katarina; Vejsova, Marcela; Carroll, James; Coffey, Aidan; Finster, Jacek; Tabak, Dominik; Niedbala, Halina; Kozik, Violetta; Polanski, Jaroslaw; Csollei, Jozef; Dohnal, Jiri

2009-03-13

In the study, a series of twelve ring-substituted 4-hydroxy-1H-quinolin-2-one derivatives were prepared. The procedures for synthesis of the compounds are presented. The compounds were analyzed using RP-HPLC to determine lipophilicity and tested for their photosynthesis-inhibiting activity using spinach (Spinacia oleracea L.) chloroplasts. All the synthesized compounds were also evaluated for antifungal activity using in vitro screening with eight fungal strains. For all the compounds, the relationships between the lipophilicity and the chemical structure of the studied compounds are discussed, as well as their structure-activity relationships (SAR).

Structure activity relationship study of curcumin analogues toward the amyloid-beta aggregation inhibitor.

PubMed

Endo, Hitoshi; Nikaido, Yuri; Nakadate, Mamiko; Ise, Satomi; Konno, Hiroyuki

2014-12-15

Inhibition of the amyloid β aggregation process could possibly prevent the onset of Alzheimer's disease. In this article, we report a structure-activity relationship study of curcumin analogues for anti amyloid β aggregation activity. Compound 7, the ideal amyloid β aggregation inhibitor in vitro among synthesized curcumin analogues, has not only potent anti amyloid β aggregation effects, but also water solubility more than 160 times that of curcumin. In addition, new approaches to improve water solubility of curcumin-type compounds are proposed. Copyright © 2014 Elsevier Ltd. All rights reserved.

SOD activity of carboxyfullerenes predicts their neuroprotective efficacy: A structure-activity study

PubMed Central

Ali, Sameh Saad; Hardt, Joshua I.; Dugan, Laura L.

2008-01-01

Superoxide radical anion is a biologically important oxidant that has been linked to tissue injury and inflammation in several diseases. Here we carried out a structure-activity study on 6 different carboxyfullerene superoxide dismutase (SOD) mimetics with distinct electronic and biophysical characteristics. Neurotoxicity via NMDA receptors, which involves intracellular superoxide, was used as a model to evaluate structure-activity relationships between reactivity towards superoxide and neuronal rescue by these drugs. A significant correlation between neuroprotection by carboxyfullerenes and their ki towards superoxide radical was observed. Computer-assistant molecular modeling demonstrated that the reactivity towards superoxide is sensitive to changes in dipole moment which are dictated not only by the number of carboxyl groups, but also by their distribution on the fullerene ball. These results indicate that the SOD activity of these cell-permeable compounds predicts neuroprotection, and establishes a structure-activity relationship to aid in future studies on the biology of superoxide across disciplines. PMID:18656425

Structure-antioxidant activity relationships of flavonoids isolated from the resinous exudate of Heliotropium sinuatum.

PubMed

Modak, Brenda; Contreras, M Leonor; González-Nilo, Fernando; Torres, René

2005-01-17

Relationships between the structural characteristics of flavonoids isolated from the resinous exudate of Heliotropium sinuatum and their antioxidant activity were studied. Radical formation energies, DeltaH of dehydrogenation and spin densities were calculated using DFT methods (B3LYP/6-31G*). Results show that studied flavonoids can be divided into two sets according to their activity. It has been found that antioxidant activity depends both on substitution pattern of hydroxyl groups of the flavonoid skeleton and the presence of an unsaturation at the C2-C3 bond. A good tendency between DeltaH of dehydrogenation and antioxidant activity was established.

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.

HomoSAR: bridging comparative protein modeling with quantitative structural activity relationship to design new peptides.

PubMed

Borkar, Mahesh R; Pissurlenkar, Raghuvir R S; Coutinho, Evans C

2013-11-15

Peptides play significant roles in the biological world. To optimize activity for a specific therapeutic target, peptide library synthesis is inevitable; which is a time consuming and expensive. Computational approaches provide a promising way to simply elucidate the structural basis in the design of new peptides. Earlier, we proposed a novel methodology termed HomoSAR to gain insight into the structure activity relationships underlying peptides. Based on an integrated approach, HomoSAR uses the principles of homology modeling in conjunction with the quantitative structural activity relationship formalism to predict and design new peptide sequences with the optimum activity. In the present study, we establish that the HomoSAR methodology can be universally applied to all classes of peptides irrespective of sequence length by studying HomoSAR on three peptide datasets viz., angiotensin-converting enzyme inhibitory peptides, CAMEL-s antibiotic peptides, and hAmphiphysin-1 SH3 domain binding peptides, using a set of descriptors related to the hydrophobic, steric, and electronic properties of the 20 natural amino acids. Models generated for all three datasets have statistically significant correlation coefficients (r(2)) and predictive r2 (r(pred)2) and cross validated coefficient ( q(LOO)2). The daintiness of this technique lies in its simplicity and ability to extract all the information contained in the peptides to elucidate the underlying structure activity relationships. The difficulties of correlating both sequence diversity and variation in length of the peptides with their biological activity can be addressed. The study has been able to identify the preferred or detrimental nature of amino acids at specific positions in the peptide sequences. Copyright © 2013 Wiley Periodicals, Inc.

THE USE OF STRUCTURE-ACTIVITY RELATIONSHIPS IN INTEGRATING THE CHEMISTRY AND TOXICOLOGY OF ENDOCRINE DISRUPTING CHEMICALS

EPA Science Inventory

Structure activity relationships (SARs) are based on the principle that structurally similar chemicals should have similar biological activity. SARs relate specifically-defined toxicological activity of chemicals to their molecular structure and physico-chemical properties. To de...

3-cyanoindole-based inhibitors of inosine monophosphate dehydrogenase: synthesis and initial structure-activity relationships.

PubMed

Dhar, T G Murali; Shen, Zhongqi; Gu, Henry H; Chen, Ping; Norris, Derek; Watterson, Scott H; Ballentine, Shelley K; Fleener, Catherine A; Rouleau, Katherine A; Barrish, Joel C; Townsend, Robert; Hollenbaugh, Diane L; Iwanowicz, Edwin J

2003-10-20

A series of novel small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH), based upon a 3-cyanoindole core, were explored. IMPDH catalyzes the rate determining step in guanine nucleotide biosynthesis and is a target for anticancer, immunosuppressive and antiviral therapy. The synthesis and the structure-activity relationships (SAR), derived from in vitro studies, for this new series of inhibitors is given.

Studies of structure-activity relationship on plant polyphenol-induced suppression of human liver cancer cells.

PubMed

Loa, Jacky; Chow, Pierce; Zhang, Kai

2009-05-01

To study anticancer activities of 68 plant polyphenols with different backbone structures and various substitutions and to analyze the structure-activity relationships. Antiproliferative activity of 68 plant polyphenols on human liver cancer cells were screened by the 3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetrazolium bromide method. Structure-activity relationships were analyzed by comparison of their activities with selected structures. Cell cycle progression was assayed by flow cytometry analysis and apoptosis was analyzed by DNA fragment assay. Based on their backbone structures, 68 polyphenols were sub-classed to flavonoids (chalcones, flavanones, flavones and isoflavones), chromones and coumarins. The order of their potency to suppress the human liver cancer cells is chalcones > flavones > chromones > isoflavones > flavanones > coumarins. Chalcones comprise the most potent group with IC(50) values ranging from 21.69 to 197 microM. Top nine most potent chalcones in the group have hydroxylation at 2'-carbon position in B-ring. Flavones ranked second in their potencies. Quercetin, 4-hydroxyflavone and luteolin are three hydroxyflavones with highest potencies in this group. Their IC(50) values are 30.81, 39.29 and 71.17 microM, respectively. Chromones, isoflavones, flavanones and coumarins showed much lower potencies when compared to the first two groups with IC(50) ranges of 61 to >400, 131 to >400, 138 to >400 and 360.85 to >400 microM, respectively. In mechanistic studies, the most potent chalcone, 2,2'-dihydroxychalcone could induce G2/M arrest and then apoptosis of the cancer cells. An analysis of structure-activity relationship showed that following structures are required for their inhibitory potencies on human liver cancer cells: (1) of the six sub-classes of the polyphenols tested, the unique backbone structure of chalcones with a open C-ring; (2) within the chalcone group, hydroxyl substitution at 2'-carbon of B-ring; (3) hydroxyl substitution at 3'-carbon in B-ring of flavones. However, some other structures were found to decrease their potencies: e.g. substitutions by sugar moieties in flavones. These data are valuable for design and modification of new polyphenols, which could be potential antiproliferative agents of cancer cells.

Depressive symptoms, lifestyle structure, and ART adherence among HIV-infected individuals: a longitudinal mediation analysis.

PubMed

Magidson, Jessica F; Blashill, Aaron J; Safren, Steven A; Wagner, Glenn J

2015-01-01

Despite the well-documented relationship between depression and antiretroviral therapy (ART) nonadherence, few studies have identified explanatory pathways through which depression affects adherence. The current study tested lifestyle structure-the degree of organization and routinization of daily activities-as a mediator of this relationship, given previous evidence of lifestyle structure being associated with both depression and ART nonadherence. HIV-infected individuals starting or re-starting ART in the California Collaborative Treatment Group 578 study (n = 199) were assessed over 48 weeks. Adherence was measured using electronic monitoring caps to determine dose timing and doses taken, and viral load was assessed. The mediating role of lifestyle structure was tested using generalized linear mixed-effects modeling and bootstrapping. Lifestyle significantly mediated the relationship between depression and both measures of ART adherence behavior. Interventions that minimize disruptions to lifestyle structure and link adherence to daily activities may be useful for individuals with depression and ART nonadherence.

Functional Evolution of PLP-dependent Enzymes based on Active-Site Structural Similarities

PubMed Central

Catazaro, Jonathan; Caprez, Adam; Guru, Ashu; Swanson, David; Powers, Robert

2014-01-01

Families of distantly related proteins typically have very low sequence identity, which hinders evolutionary analysis and functional annotation. Slowly evolving features of proteins, such as an active site, are therefore valuable for annotating putative and distantly related proteins. To date, a complete evolutionary analysis of the functional relationship of an entire enzyme family based on active-site structural similarities has not yet been undertaken. Pyridoxal-5’-phosphate (PLP) dependent enzymes are primordial enzymes that diversified in the last universal ancestor. Using the Comparison of Protein Active Site Structures (CPASS) software and database, we show that the active site structures of PLP-dependent enzymes can be used to infer evolutionary relationships based on functional similarity. The enzymes successfully clustered together based on substrate specificity, function, and three-dimensional fold. This study demonstrates the value of using active site structures for functional evolutionary analysis and the effectiveness of CPASS. PMID:24920327

Functional evolution of PLP-dependent enzymes based on active-site structural similarities.

PubMed

Catazaro, Jonathan; Caprez, Adam; Guru, Ashu; Swanson, David; Powers, Robert

2014-10-01

Families of distantly related proteins typically have very low sequence identity, which hinders evolutionary analysis and functional annotation. Slowly evolving features of proteins, such as an active site, are therefore valuable for annotating putative and distantly related proteins. To date, a complete evolutionary analysis of the functional relationship of an entire enzyme family based on active-site structural similarities has not yet been undertaken. Pyridoxal-5'-phosphate (PLP) dependent enzymes are primordial enzymes that diversified in the last universal ancestor. Using the comparison of protein active site structures (CPASS) software and database, we show that the active site structures of PLP-dependent enzymes can be used to infer evolutionary relationships based on functional similarity. The enzymes successfully clustered together based on substrate specificity, function, and three-dimensional-fold. This study demonstrates the value of using active site structures for functional evolutionary analysis and the effectiveness of CPASS. © 2014 Wiley Periodicals, Inc.

Function-Oriented Synthesis: How to Design Simplified Analogues of Antibacterial Nucleoside Natural Products?

PubMed

Ichikawa, Satoshi

2016-06-01

It is important to pursue function-oriented synthesis (FOS), a strategy for the design of less structurally complex targets with comparable or superior activity that can be made in a practical manner, because compared to synthetic drugs, many biologically relevant natural products possess large and complex chemical structures that may restrict chemical modifications in a structure-activity relationship study. In this account, we describe recent efforts to simplify complex nucleoside natural products including caprazamycins. Considering the structure-activity relationship study with several truncated analogues, three types of simplified derivatives, namely, oxazolidine, isoxazolidine, and lactam-fused isoxazolidine-containing uridine derivatives, were designed and efficiently synthesized. These simplified derivatives have exhibited promising antibacterial activities. A significant feature of our studies is the rational and drastic simplification of the molecular architecture of caprazamycins. This study provides a novel strategy for the development of a new type of antibacterial agent effective against drug-resistant bacteria. © 2016 The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Structure-activity relationships of tetramethylpiperidine-substituted phenazines against Mycobacterium leprae in vitro.

PubMed Central

Franzblau, S G; White, K E; O'Sullivan, J F

1989-01-01

In a previous study of structure-activity relationships of selected phenazines against Mycobacterium leprae in vitro, compounds containing a 2,2,6,6-tetramethylpiperidine substitution at the imino nitrogen were most active. Therefore, the effect of substitution at the para positions of the phenyl and anilino groups in tetramethylpiperidine-substituted phenazines was assessed. As determined by radiorespirometry, activity in ascending order was observed in compounds substituted with hydrogens or fluorines, ethoxy groups, methyl groups, chlorines, and bromines and correlated with partition coefficients in octanol-water. PMID:2692516

Discovery of imidazo[1,2-b]pyridazine derivatives as IKKbeta inhibitors. Part 1: Hit-to-lead study and structure-activity relationship.

PubMed

Shimizu, Hiroki; Tanaka, Shinji; Toki, Tadashi; Yasumatsu, Isao; Akimoto, Toshihiko; Morishita, Kaoru; Yamasaki, Tomonori; Yasukochi, Takanori; Iimura, Shin

2010-09-01

Imidazo[1,2-b]pyridazine derivatives from high-throughput screening were developed as IKKbeta inhibitors. By the optimization of the 3- and 6-position of imidazo[1,2-b]pyridazine scaffold, cell-free IKKbeta inhibitory activity and TNFalpha inhibitory activity in THP-1 cell increased. Also, these compounds showed high kinase selectivity. The structure-activity relationship was revealed and the interaction model of imidazo[1,2-b]pyridazine compounds with IKKbeta was constructed. Copyright 2010. Published by Elsevier Ltd.

Redox properties of structural Fe in clay minerals: 3. Relationships between smectite redox and structural properties.

PubMed

Gorski, Christopher A; Klüpfel, Laura E; Voegelin, Andreas; Sander, Michael; Hofstetter, Thomas B

2013-01-01

Structural Fe in clay minerals is an important redox-active species in many pristine and contaminated environments as well as in engineered systems. Understanding the extent and kinetics of redox reactions involving Fe-bearing clay minerals has been challenging due to the inability to relate structural Fe(2+)/Fe(total) fractions to fundamental redox properties, such as reduction potentials (EH). Here, we overcame this challenge by using mediated electrochemical reduction (MER) and oxidation (MEO) to characterize the fraction of redox-active structural Fe (Fe(2+)/Fe(total)) in smectites over a wide range of applied EH-values (-0.6 V to +0.6 V). We examined Fe(2+)/Fe(total )- EH relationships of four natural Fe-bearing smectites (SWy-2, SWa-1, NAu-1, NAu-2) in their native, reduced, and reoxidized states and compared our measurements with spectroscopic observations and a suite of mineralogical properties. All smectites exhibited unique Fe(2+)/Fe(total) - EH relationships, were redox active over wide EH ranges, and underwent irreversible electron transfer induced structural changes that were observable with X-ray absorption spectroscopy. Variations among the smectite Fe(2+)/Fe(total) - EH relationships correlated well with both bulk and molecular-scale properties, including Fe(total) content, layer charge, and quadrupole splitting values, suggesting that multiple structural parameters determined the redox properties of smectites. The Fe(2+)/Fe(total) - EH relationships developed for these four commonly studied clay minerals may be applied to future studies interested in relating the extent of structural Fe reduction or oxidation to EH-values.

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.

An overview of structure-activity relationship studies of curcumin analogs as antioxidant and anti-inflammatory agents.

PubMed

Arshad, Laiba; Haque, Md Areeful; Abbas Bukhari, Syed Nasir; Jantan, Ibrahim

2017-04-01

Curcumin, extracted mainly from Curcuma longa rhizomes, has been reported to possess potent anti-inflammatory and anti-oxidant activities. Although safe at higher doses and exhibiting multiple biological activities, curcumin still has the problem of poor bioavailability which has been an attractive area of research over the last few years. A number of efforts have been made by modifying structural features of curcumin. This review highlights the structurally modified and more stable newly synthesized curcumin analogs that have been screened against antioxidant and anti-inflammatory activities. Also the structure-activity relationship to gain insight into future guidelines for scheming new compounds has been discussed, and further these analogs being more stable may serve as promising agents for use in different pathological conditions.

High Add Valued Application of Turpentine in Crop Production through Structural Modification and QSAR Analysis.

PubMed

Gao, Yanqing; Li, Jingjing; Li, Jian; Song, Zhanqian; Shang, Shibin; Rao, Xiaoping

2018-02-08

Turpentine is a volatile component of resin, which is an abundant forest resource in Southern China. As one of the most important components, the integrated application of β-pinene has been studied. The broad-spectrum evaluation of β-pinene and its analogues has, therefore, been necessary. In an attempt to expand the scope of agro-activity trials, the preparation and the evaluation of the herbicidal activity of a series of β-pinene analogues against three agricultural herbs were carried out. In accordance with the overall herbicidal activity, it is noteworthy that compounds 6k , 6l , and 6m demonstrated extreme activity with IC 50 values of 0.065, 0.065, and 0.052 mol active ingredients/hectare against E. crus-galli . The preliminary structure-activity relationship (SAR) was analyzed and the compounds with the appropriate volatility and substituent type that had beneficial herbicidal activity were analyzed. Simultaneously, the quantitative structure-activity relationship (QSAR) model was built and the most important structural features were indicated, which was, to a certain extent, in line with the SAR study. The study aimed to study the application of the forest resource turpentine in agriculture as a potential and alternative approach for comprehensive utilization.

Rational design, synthesis, biologic evaluation, and structure-activity relationship studies of novel 1-indanone alpha(1)-adrenoceptor antagonists.

PubMed

Li, Minyong; Xia, Lin

2007-11-01

In the present report, a novel series of 1-indanone alpha(1)-adrenoceptor antagonists were designed and synthesized based on 3D-pharmacophore model. Their in vitro alpha(1)-adrenoceptor antagonistic assay showed that three compounds (2a, 2m, and 2o) had similar or improved alpha(1)-adrenoceptor antagonistic activities relative to the positive control prazosin. Based on these results, a three-dimensional quantitative structure-activity relationship study was performed using a Self-Organizing Molecular Field Analysis method to provide insight for the future development of alpha(1)-adrenoceptor antagonists.

Structure-activity relationship of crustacean peptide hormones.

PubMed

Katayama, Hidekazu

2016-01-01

In crustaceans, various physiological events, such as molting, vitellogenesis, and sex differentiation, are regulated by peptide hormones. To understanding the functional sites of these hormones, many structure-activity relationship (SAR) studies have been published. In this review, the author focuses the SAR of crustacean hyperglycemic hormone-family peptides and androgenic gland hormone and describes the detailed results of our and other research groups. The future perspectives will be also discussed.

Antibacterial Activity of Polyphenols: Structure-Activity Relationship and Influence of Hyperglycemic Condition.

PubMed

Xie, Yixi; Chen, Jing; Xiao, Aiping; Liu, Liangliang

2017-11-06

Polyphenols are plant-derived natural products with well-documented health benefits to human beings, such as antibacterial activities. However, the antibacterial activities of polyphenols under hyperglycemic conditions have been rarely studied, which could be relevant to their antibacterial efficacy in disease conditions, such as in diabetic patients. Herein, the antibacterial activities of 38 polyphenols under mimicked hyperglycemic conditions were evaluated. The structure-antibacterial activity relationships of polyphenols were also tested and analyzed. The presence of glucose apparently promoted the growth of the bacterial strains tested in this study. The OD600 values of tested bacteria strains increased from 1.09-fold to 1.49-fold by adding 800 mg/dL glucose. The polyphenols showed structurally dependent antibacterial activities, which were significantly impaired under the hyperglycemic conditions. The results from this study indicated that high blood glucose might promote bacterial infection, and the hyperglycemic conditions resulting from diabetes were likely to suppress the antibacterial benefits of polyphenols.

3D-quantitative structure-activity relationship studies on benzothiadiazepine hydroxamates as inhibitors of tumor necrosis factor-alpha converting enzyme.

PubMed

Murumkar, Prashant R; Giridhar, Rajani; Yadav, Mange Ram

2008-04-01

A set of 29 benzothiadiazepine hydroxamates having selective tumor necrosis factor-alpha converting enzyme inhibitory activity were used to compare the quality and predictive power of 3D-quantitative structure-activity relationship, comparative molecular field analysis, and comparative molecular similarity indices models for the atom-based, centroid/atom-based, data-based, and docked conformer-based alignment. Removal of two outliers from the initial training set of molecules improved the predictivity of models. Among the 3D-quantitative structure-activity relationship models developed using the above four alignments, the database alignment provided the optimal predictive comparative molecular field analysis model for the training set with cross-validated r(2) (q(2)) = 0.510, non-cross-validated r(2) = 0.972, standard error of estimates (s) = 0.098, and F = 215.44 and the optimal comparative molecular similarity indices model with cross-validated r(2) (q(2)) = 0.556, non-cross-validated r(2) = 0.946, standard error of estimates (s) = 0.163, and F = 99.785. These models also showed the best test set prediction for six compounds with predictive r(2) values of 0.460 and 0.535, respectively. The contour maps obtained from 3D-quantitative structure-activity relationship studies were appraised for activity trends for the molecules analyzed. The comparative molecular similarity indices models exhibited good external predictivity as compared with that of comparative molecular field analysis models. The data generated from the present study helped us to further design and report some novel and potent tumor necrosis factor-alpha converting enzyme inhibitors.

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.

THE PRACTICE OF STRUCTURE ACTIVITY RELATIONSHIPS (SAR) IN TOXICOLOGY

EPA Science Inventory

Both qualitative and quantitative modeling methods relating chemical structure to biological activity, called structure-activity relationship analyses or SAR, are applied to the prediction and characterization of chemical toxicity. This minireview will discuss some generic issue...

Structure-activity relationship studies of chalcone leading to 3-hydroxy-4,3',4',5'-tetramethoxychalcone and its analogues as potent nuclear factor kappaB inhibitors and their anticancer activities.

PubMed

Srinivasan, Balasubramanian; Johnson, Thomas E; Lad, Rahul; Xing, Chengguo

2009-11-26

Chalcone is a privileged structure, demonstrating promising anti-inflammatory and anticancer activities. One potential mechanism is to suppress nuclear factor kappa B (NF-kappaB) activation. The structures of chalcone-based NF-kappaB inhibitors vary significantly that there is minimum information about their structure-activity relationships (SAR). This study aims to establish SAR of chalcone-based compounds to NF-kappaB inhibition, to explore the feasibility of developing simple chalcone-based potent NF-kappaB inhibitors, and to evaluate their anticancer activities. Three series of chalcones were synthesized in one to three steps with the key step being aldol condensation. These candidates demonstrated a wide range of NF-kappaB inhibitory activities, some of low micromolar potency, establishing that structural complexity is not required for NF-kappaB inhibition. Lead compounds also demonstrate potent cytotoxicity against lung cancer cells. Their cytotoxicities correlate moderately well with their NF-kappaB inhibitory activities, suggesting that suppressing NF-kappaB activation is likely responsible for at least some of the cytotoxicities. One lead compound effectively inhibits lung tumor growth with no signs of adverse side effects.

Biological activity of antitumoural MGBG: the structural variable.

PubMed

Marques, M P M; Gil, F P S C; Calheiros, R; Battaglia, V; Brunati, A M; Agostinelli, E; Toninello, A

2008-05-01

The present study aims at determining the structure-activity relationships (SAR's) ruling the biological function of MGBG (methylglyoxal bis(guanylhydrazone)), a competitive inhibitor of S-adenosyl-L-methionine decarboxylase displaying anticancer activity, involved in the biosynthesis of the naturally occurring polyamines spermidine and spermine. In order to properly understand its biochemical activity, MGBG's structural preferences at physiological conditions were ascertained, by quantum mechanical (DFT) calculations.

Structure-activity relationship of prenyl-substituted polyphenols from Artocarpus heterophyllus as inhibitors of melanin biosynthesis in cultured melanoma cells.

PubMed

Arung, Enos Tangke; Shimizu, Kuniyoshi; Kondo, Ryuichiro

2007-09-01

A series of prenylated, flavone-based polyphenols, compounds 1-8, were isolated from the wood of Artocarpus heterophyllus. These compounds, which have previously been shown not to inhibit tyrosinase activity, were found to be active inhibitors of the in vivo melanin biosynthesis in B16 melanoma cells, with little or no cytotoxicity. To clarify the structural requirement for inhibition, some structure-activity relationships were studied, in comparison with related compounds lacking prenyl side chains. Our experiments indicate that both prenyl and OH groups, as well as the type of substitution pattern, are crucial for the inhibition of melanin production in B16 melanoma cells.

Quantitative structure-activation barrier relationship modeling for Diels-Alder ligations utilizing quantum chemical structural descriptors.

PubMed

Nandi, Sisir; Monesi, Alessandro; Drgan, Viktor; Merzel, Franci; Novič, Marjana

2013-10-30

In the present study, we show the correlation of quantum chemical structural descriptors with the activation barriers of the Diels-Alder ligations. A set of 72 non-catalysed Diels-Alder reactions were subjected to quantitative structure-activation barrier relationship (QSABR) under the framework of theoretical quantum chemical descriptors calculated solely from the structures of diene and dienophile reactants. Experimental activation barrier data were obtained from literature. Descriptors were computed using Hartree-Fock theory using 6-31G(d) basis set as implemented in Gaussian 09 software. Variable selection and model development were carried out by stepwise multiple linear regression methodology. Predictive performance of the quantitative structure-activation barrier relationship (QSABR) model was assessed by training and test set concept and by calculating leave-one-out cross-validated Q2 and predictive R2 values. The QSABR model can explain and predict 86.5% and 80% of the variances, respectively, in the activation energy barrier training data. Alternatively, a neural network model based on back propagation of errors was developed to assess the nonlinearity of the sought correlations between theoretical descriptors and experimental reaction barriers. A reasonable predictability for the activation barrier of the test set reactions was obtained, which enabled an exploration and interpretation of the significant variables responsible for Diels-Alder interaction between dienes and dienophiles. Thus, studies in the direction of QSABR modelling that provide efficient and fast prediction of activation barriers of the Diels-Alder reactions turn out to be a meaningful alternative to transition state theory based computation.

Quantitative structure-property relationship (correlation analysis) of phosphonic acid-based chelates in design of MRI contrast agent.

PubMed

Tiwari, Anjani K; Ojha, Himanshu; Kaul, Ankur; Dutta, Anupama; Srivastava, Pooja; Shukla, Gauri; Srivastava, Rakesh; Mishra, Anil K

2009-07-01

Nuclear magnetic resonance imaging is a very useful tool in modern medical diagnostics, especially when gadolinium (III)-based contrast agents are administered to the patient with the aim of increasing the image contrast between normal and diseased tissues. With the use of soft modelling techniques such as quantitative structure-activity relationship/quantitative structure-property relationship after a suitable description of their molecular structure, we have studied a series of phosphonic acid for designing new MRI contrast agent. Quantitative structure-property relationship studies with multiple linear regression analysis were applied to find correlation between different calculated molecular descriptors of the phosphonic acid-based chelating agent and their stability constants. The final quantitative structure-property relationship mathematical models were found as--quantitative structure-property relationship Model for phosphonic acid series (Model 1)--log K(ML) = {5.00243(+/-0.7102)}- MR {0.0263(+/-0.540)}n = 12 l r l = 0.942 s = 0.183 F = 99.165 quantitative structure-property relationship Model for phosphonic acid series (Model 2)--log K(ML) = {5.06280(+/-0.3418)}- MR {0.0252(+/- .198)}n = 12 l r l = 0.956 s = 0.186 F = 99.256.

Synthesis, cytotoxicity and haemolytic activity of Pulsatilla saponin A, D derivatives.

PubMed

Chen, Zhong; Duan, Huaqing; Wang, Minglei; Han, Li; Liu, Yanli; Zhu, Yongming; Yang, Shilin

2015-06-15

The strong haemolytic activity of Pulsatilla saponin A (PSA), D (PSD) hampered their clinical development of antitumor agents. In order to solve this problem, C-28 position modification derivatives of PSA/PSD were synthesized. The cytotoxicity and haemolytic activity of these compounds were evaluated. Structure-activity relationship and structure-toxicity relationship had been observed. The mice acute toxicity of compound 11 was reduced greatly than that of PSA. This study indicates that compound 11 may represent an interesting class of potent antitumor agents from triterpenoid saponins avoiding the haemolysis problem. The present study has important significance for the development of antitumor saponins. Copyright © 2015 Elsevier Ltd. All rights reserved.

Social Relationships, Leisure Activity, and Health in Older Adults

PubMed Central

Chang, Po-Ju; Wray, Linda; Lin, Yeqiang

2015-01-01

Objective Although the link between enhanced social relationships and better health has generally been well established, few studies have examined the role of leisure activity in this link. This study examined how leisure influences the link between social relationships and health in older age. Methods Using data from the 2006 and 2010 waves of the nationally representative U.S. Health and Retirement Study and structural equation modelling analyses, we examined data on 2,965 older participants to determine if leisure activities mediated the link between social relationships and health in 2010, controlling for race, education level, and health in 2006. Results The results demonstrated that leisure activities mediate the link between social relationships and health in these age groups. Perceptions of positive social relationships were associated with greater involvement in leisure activities, and greater involvement in leisure activities was associated with better health in older age. Discussion & Conclusions The contribution of leisure to health in these age groups is receiving increasing attention, and the results of this study add to the literature on this topic, by identifying the mediating effect of leisure activity on the link between social relationships and health. Future studies aimed at increasing leisure activity may contribute to improved health outcomes in older adults. PMID:24884905

Social relationships, leisure activity, and health in older adults.

PubMed

Chang, Po-Ju; Wray, Linda; Lin, Yeqiang

2014-06-01

Although the link between enhanced social relationships and better health has generally been well established, few studies have examined the role of leisure activity in this link. This study examined how leisure influences the link between social relationships and health in older age. Using data from the 2006 and 2010 waves of the nationally representative U.S. Health and Retirement Study and structural equation modeling analyses, we examined data on 2,965 older participants to determine if leisure activities mediated the link between social relationships and health in 2010, controlling for race, education level, and health in 2006. The results demonstrated that leisure activities mediate the link between social relationships and health in these age groups. Perceptions of positive social relationships were associated with greater involvement in leisure activities, and greater involvement in leisure activities was associated with better health in older age. The contribution of leisure to health in these age groups is receiving increasing attention, and the results of this study add to the literature on this topic, by identifying the mediating effect of leisure activity on the link between social relationships and health. Future studies aimed at increasing leisure activity may contribute to improved health outcomes in older adults. PsycINFO Database Record (c) 2014 APA, all rights reserved.

Synthesis, structure-activity relationships, and in vivo evaluation of N3-phenylpyrazinones as novel corticotropin-releasing factor-1 (CRF1) receptor antagonists.

PubMed

Hartz, Richard A; Ahuja, Vijay T; Arvanitis, Argyrios G; Rafalski, Maria; Yue, Eddy W; Denhart, Derek J; Schmitz, William D; Ditta, Jonathan L; Deskus, Jeffrey A; Brenner, Allison B; Hobbs, Frank W; Payne, Joseph; Lelas, Snjezana; Li, Yu-Wen; Molski, Thaddeus F; Mattson, Gail K; Peng, Yong; Wong, Harvey; Grace, James E; Lentz, Kimberley A; Qian-Cutrone, Jingfang; Zhuo, Xiaoliang; Shu, Yue-Zhong; Lodge, Nicholas J; Zaczek, Robert; Combs, Andrew P; Olson, Richard E; Bronson, Joanne J; Mattson, Ronald J; Macor, John E

2009-07-23

Evidence suggests that corticotropin-releasing factor-1 (CRF(1)) receptor antagonists may offer therapeutic potential for the treatment of diseases associated with elevated levels of CRF such as anxiety and depression. A pyrazinone-based chemotype of CRF(1) receptor antagonists was discovered. Structure-activity relationship studies led to the identification of numerous potent analogues including 12p, a highly potent and selective CRF(1) receptor antagonist with an IC(50) value of 0.26 nM. The pharmacokinetic properties of 12p were assessed in rats and Cynomolgus monkeys. Compound 12p was efficacious in the defensive withdrawal test (an animal model of anxiety) in rats. The synthesis, structure-activity relationships and in vivo properties of compounds within the pyrazinone chemotype are described.

Syntheses and anti-MRSA activities of the C3 analogs of mansonone F, a potent anti-bacterial sesquiterpenoid: insights into its structural requirements for anti-MRSA activity.

PubMed

Shin, Dong-Yun; Kim, Sun Nam; Chae, Jung-Hyun; Hyun, Soon-Sil; Seo, Seung-Yong; Lee, Yong-Sil; Lee, Kwang-Ok; Kim, Seok-Ho; Lee, Yun-Sang; Jeong, Jae Min; Choi, Nam-Song; Suh, Young-Ger

2004-09-06

Syntheses and excellent anti-MRSA activities of the mansonone F analogs are reported. In addition, the minimal structural requirements for its anti-MRSA activities as well as its structure-activity relationship including the C3 substituents effects on anti-MRSA activity are also described. In particular, this study revealed that both ortho-quinone and tricyclic systems of mansonone F are essential for anti-MRSA activities.

Quantitative studies on structure-DPPH• scavenging activity relationships of food phenolic acids.

PubMed

Jing, Pu; Zhao, Shu-Juan; Jian, Wen-Jie; Qian, Bing-Jun; Dong, Ying; Pang, Jie

2012-11-01

Phenolic acids are potent antioxidants, yet the quantitative structure-activity relationships of phenolic acids remain unclear. The purpose of this study was to establish 3D-QSAR models able to predict phenolic acids with high DPPH• scavenging activity and understand their structure-activity relationships. The model has been established by using a training set of compounds with cross-validated q2 = 0.638/0.855, non-cross-validated r2 = 0.984/0.986, standard error of estimate = 0.236/0.216, and F = 139.126/208.320 for the best CoMFA/CoMSIA models. The predictive ability of the models was validated with the correlation coefficient r2(pred) = 0.971/0.996 (>0.6) for each model. Additionally, the contour map results suggested that structural characteristics of phenolics acids favorable for the high DPPH• scavenging activity might include: (1) bulky and/or electron-donating substituent groups on the phenol ring; (2) electron-donating groups at the meta-position and/or hydrophobic groups at the meta-/ortho-position; (3) hydrogen-bond donor/electron-donating groups at the ortho-position. The results have been confirmed based on structural analyses of phenolic acids and their DPPH• scavenging data from eight recent publications. The findings may provide deeper insight into the antioxidant mechanisms and provide useful information for selecting phenolic acids for free radical scavenging properties.

The power of social networks and social support in promotion of physical activity and body mass index among African American adults.

PubMed

Flórez, Karen R; Richardson, Andrea S; Ghosh-Dastidar, Madhumita Bonnie; Troxel, Wendy; DeSantis, Amy; Colabianchi, Natalie; Dubowitz, Tamara

2018-04-01

Social support and social networks can elucidate important structural and functional aspects of social relationships that are associated with health-promoting behaviors, including Physical Activity (PA) and weight. A growing number of studies have investigated the relationship between social support, social networks, PA and obesity specifically among African Americans; however, the evidence is mixed and many studies focus exclusively on African American women. Most studies have also focused on either functional or structural aspects of social relationships (but not both) and few have objectively measured moderate-to-vigorous physical activity (MVPA) and body mass index (BMI). Cross-sectional surveys of adult African American men and women living in two low-income predominantly African American neighborhoods in Pittsburgh, PA (N = 799) measured numerous structural features as well as functional aspects of social relationships. Specifically, structural features included social isolation, and social network size and diversity. Functional aspects included perceptions of social support for physical activity from the social network in general as well as from family and friends specifically. Height, weight, and PA were objectively measured. From these, we derived Body Mass Index (BMI) and moderate-to-vigorous physical activity (MVPA). All regression models were stratified by gender, and included age, income, education, employment, marital status, physical limitations, and a neighborhood indicator. Greater social isolation was a significant predictor of lower BMI among men only. Among women only, social isolation was significantly associated with increased MVPA whereas, network diversity was significantly associated with reduced MVPA. Future research would benefit from in-depth qualitative investigations to understand how social networks may act to influence different types of physical activity among African Americans, as well as understand how they can be possible levers for health promotion and prevention.

NMR Studies of Structure-Reactivity Relationships in Carbonyl Reduction: A Collaborative Advanced Laboratory Experiment

ERIC Educational Resources Information Center

Marincean, Simona; Smith, Sheila R.; Fritz, Michael; Lee, Byung Joo; Rizk, Zeinab

2012-01-01

An upper-division laboratory project has been developed as a collaborative investigation of a reaction routinely taught in organic chemistry courses: the reduction of carbonyl compounds by borohydride reagents. Determination of several trends regarding structure-activity relationship was possible because each student contributed his or her results…

The effect of hippocampal function, volume and connectivity on posterior cingulate cortex functioning during episodic memory fMRI in mild cognitive impairment.

PubMed

Papma, Janne M; Smits, Marion; de Groot, Marius; Mattace Raso, Francesco U; van der Lugt, Aad; Vrooman, Henri A; Niessen, Wiro J; Koudstaal, Peter J; van Swieten, John C; van der Veen, Frederik M; Prins, Niels D

2017-09-01

Diminished function of the posterior cingulate cortex (PCC) is a typical finding in early Alzheimer's disease (AD). It is hypothesized that in early stage AD, PCC functioning relates to or reflects hippocampal dysfunction or atrophy. The aim of this study was to examine the relationship between hippocampus function, volume and structural connectivity, and PCC activation during an episodic memory task-related fMRI study in mild cognitive impairment (MCI). MCI patients (n = 27) underwent episodic memory task-related fMRI, 3D-T1w MRI, 2D T2-FLAIR MRI and diffusion tensor imaging. Stepwise linear regression analysis was performed to examine the relationship between PCC activation and hippocampal activation, hippocampal volume and diffusion measures within the cingulum along the hippocampus. We found a significant relationship between PCC and hippocampus activation during successful episodic memory encoding and correct recognition in MCI patients. We found no relationship between the PCC and structural hippocampal predictors. Our results indicate a relationship between PCC and hippocampus activation during episodic memory engagement in MCI. This may suggest that during episodic memory, functional network deterioration is the most important predictor of PCC functioning in MCI. • PCC functioning during episodic memory relates to hippocampal functioning in MCI. • PCC functioning during episodic memory does not relate to hippocampal structure in MCI. • Functional network changes are an important predictor of PCC functioning in MCI.

Structural optimization and structure-functional selectivity relationship studies of G protein-biased EP2 receptor agonists.

PubMed

Ogawa, Seiji; Watanabe, Toshihide; Moriyuki, Kazumi; Goto, Yoshikazu; Yamane, Shinsaku; Watanabe, Akio; Tsuboi, Kazuma; Kinoshita, Atsushi; Okada, Takuya; Takeda, Hiroyuki; Tani, Kousuke; Maruyama, Toru

2016-05-15

The modification of the novel G protein-biased EP2 agonist 1 has been investigated to improve its G protein activity and develop a better understanding of its structure-functional selectivity relationship (SFSR). The optimization of the substituents on the phenyl ring of 1, followed by the inversion of the hydroxyl group on the cyclopentane moiety led to compound 9, which showed a 100-fold increase in its G protein activity compared with 1 without any increase in β-arrestin recruitment. Furthermore, SFSR studies revealed that the combination of meta and para substituents on the phenyl moiety was crucial to the functional selectivity. Copyright © 2016 Elsevier Ltd. All rights reserved.

Phomentrioloxin, a fungal phytotoxin with potential herbicidal activity, and its derivatives: a structure-activity relationship study.

PubMed

Cimmino, Alessio; Andolfi, Anna; Zonno, Maria Chiara; Boari, Angela; Troise, Ciro; Motta, Andrea; Vurro, Maurizio; Ash, Gavin; Evidente, Antonio

2013-10-09

Phomentrioloxin is a phytotoxic geranylcyclohexenetriol produced in liquid culture by Phomopsis sp. (teleomorph: Diaporthe gulyae), a potential mycoherbicide proposed for the control of the annual weed Carthamus lanatus. In this study, seven derivatives obtained by chemical modifications of the toxin were assayed for phytotoxic, antimicrobial, and zootoxic activities, and the structure-activity relationships were examined. Each compound was tested on nonhost weedy and agrarian plants, fungi, Gram+ and Gram- bacteria, and on brine shrimp larvae. The results provide insights into an investigation of the structural requirements for activity. The hydroxy groups at C-2 and C-4 appeared to be important features for the phytotoxicity, as well as an unchanged cyclohexentriol ring. A role seemed also to be played by the unsaturations of the geranyl side chain. These findings could be useful for understanding the mechanisms of action of new natural products, for identifying the active sites, and possibly in devising new herbicides of natural origin.

Structure-activity relationships between sterols and their thermal stability in oil matrix.

PubMed

Hu, Yinzhou; Xu, Junli; Huang, Weisu; Zhao, Yajing; Li, Maiquan; Wang, Mengmeng; Zheng, Lufei; Lu, Baiyi

2018-08-30

Structure-activity relationships between 20 sterols and their thermal stabilities were studied in a model oil system. All sterol degradations were found to be consistent with a first-order kinetic model with determination of coefficient (R 2 ) higher than 0.9444. The number of double bonds in the sterol structure was negatively correlated with the thermal stability of sterol, whereas the length of the branch chain was positively correlated with the thermal stability of sterol. A quantitative structure-activity relationship (QSAR) model to predict thermal stability of sterol was developed by using partial least squares regression (PLSR) combined with genetic algorithm (GA). A regression model was built with R 2 of 0.806. Almost all sterol degradation constants can be predicted accurately with R 2 of cross-validation equals to 0.680. Four important variables were selected in optimal QSAR model and the selected variables were observed to be related with information indices, RDF descriptors, and 3D-MoRSE descriptors. Copyright © 2018 Elsevier Ltd. All rights reserved.

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.

Proximal and Distal Outcomes of Organizational Socialization among New Teachers: A Mediation Analysis

ERIC Educational Resources Information Center

Tengku Ariffin, Tengku Faekah; Awang Hashim, Rosna; Yusof, Norhafezah

2014-01-01

This study was designed to examine the relationship between socialization experience and the task performance of new teachers. It proposed to do this by testing a structural model. In explicating the relationship between the two constructs, teacher engagement in workplace learning activities and wellbeing were included in the structural model as…

Structure-activity relationships on the study of β-galactosidase folding/unfolding due to interactions with immobilization additives: Triton X-100 and ethanol.

PubMed

Soto, Dayana; Escobar, Sindy; Guzmán, Fanny; Cárdenas, Constanza; Bernal, Claudia; Mesa, Monica

2017-03-01

Improving the enzyme stability is a challenge for allowing their practical application. The surfactants are stabilizing agents, however, there are still questions about their influence on enzyme properties. The structure-activity/stability relationship for β-galactosidase from Bacillus circulans is studied here by Circular Dichroism and activity measurements, as a function of temperature and pH. The tendency of preserving the β-sheet and α-helix structures at temperatures below 65°C and different pH is the result of the balance between the large- and short-range effects, respecting to the active site. This information is fundamental for explaining the structural changes of this enzyme in the presence of Triton X-100 surfactant and ethanol. The enzyme thermal stabilization in the presence of this surfactant responds to the rearrangement of the secondary structure for having optimal activity/stability. The effect of ethanol is more related with changes in the dielectric properties of the aqueous solution than with protein structural transformations. These results contribute to understand the effects of surfactant-enzyme interactions on the enzyme behavior, from the structural point of view and to rationalize the surfactant-based stabilizing strategies for β-galactosidades. Copyright © 2016 Elsevier B.V. All rights reserved.

Synthesis-Structure-Activity Relationships in Co3O4 Catalyzed CO Oxidation

NASA Astrophysics Data System (ADS)

Mingle, Kathleen; Lauterbach, Jochen

2018-05-01

In this work, a statistical design and analysis platform was used to develop cobalt oxide based oxidation catalysts prepared via one pot metal salt reduction. An emphasis was placed upon understanding the effects of synthesis conditions, such as heating regimen and Co2+ concentration on the metal salt reduction mechanism, the resultant nanomaterial properties (i.e. size, crystal structure, and crystal faceting), and the catalytic activity in CO oxidation. This was accomplished by carrying out XRD, TEM, and FTIR studies on synthesis intermediates and products. Additionally, high-throughput experimentation was employed to study the performance of Co3O4 oxidation catalysts over a wide range of reaction conditions using a 16-channel fixed bed reactor equipped with a parallel infrared imaging system. Specifically, Co3O4 nanomaterials of varying properties were evaluated for their performance as CO oxidation catalysts. Figure-of-merits including light-off temperatures and activation energies were measured and mapped back to the catalyst properties and synthesis conditions. Statistical analysis methods were used to elucidate significant property-activity relationships as well as the design rules relevant in the synthesis of active catalysts. It was found that CO oxidation light off temperatures could be decreased to <90°C by utilizing the discovered synthesis-structure-activity relationships.

Inhibition of Angiotensin-Converting Enzyme Activity by Flavonoids: Structure-Activity Relationship Studies

PubMed Central

Guerrero, Ligia; Castillo, Julián; Quiñones, Mar; Garcia-Vallvé, Santiago; Arola, Lluis; Pujadas, Gerard; Muguerza, Begoña

2012-01-01

Previous studies have demonstrated that certain flavonoids can have an inhibitory effect on angiotensin-converting enzyme (ACE) activity, which plays a key role in the regulation of arterial blood pressure. In the present study, 17 flavonoids belonging to five structural subtypes were evaluated in vitro for their ability to inhibit ACE in order to establish the structural basis of their bioactivity. The ACE inhibitory (ACEI) activity of these 17 flavonoids was determined by fluorimetric method at two concentrations (500 µM and 100 µM). Their inhibitory potencies ranged from 17 to 95% at 500 µM and from 0 to 57% at 100 µM. In both cases, the highest ACEI activity was obtained for luteolin. Following the determination of ACEI activity, the flavonoids with higher ACEI activity (i.e., ACEI >60% at 500 µM) were selected for further IC50 determination. The IC50 values for luteolin, quercetin, rutin, kaempferol, rhoifolin and apigenin K were 23, 43, 64, 178, 183 and 196 µM, respectively. Our results suggest that flavonoids are an excellent source of functional antihypertensive products. Furthermore, our structure-activity relationship studies show that the combination of sub-structures on the flavonoid skeleton that increase ACEI activity is made up of the following elements: (a) the catechol group in the B-ring, (b) the double bond between C2 and C3 at the C-ring, and (c) the cetone group in C4 at the C-ring. Protein-ligand docking studies are used to understand the molecular basis for these results. PMID:23185345

Chalcones: structural requirements for antioxidant, estrogenic and antiproliferative activities.

PubMed

Calliste, C A; Le Bail, J C; Trouillas, P; Pouget, C; Habrioux, G; Chulia, A J; Duroux, J L

2001-01-01

Flavonoids are largely studied for their biological properties and particularly for their scavenging and antioxidant activities. In the present study, we first evaluated the antioxidant and the estrogenic actions of chalcones, then we tested their effects on MCF-7 cell proliferation. Chalcones are unique in the flavonoids family in lacking a heterocyclic C ring. We tested substituted chalcones with different numbers and different positions of the hydroxy groups: 2'-hydroxychalcone, 4'-hydroxychalcone, 4-hydroxychalcone, 2',4-dihydroxychalcone, isoliquiritigenin, 2',4'-dihydroxychalcone, phloretin and naringenin chalcone. For the antioxidant tests we established the importance of the alpha-beta double bond and the 6'-hydroxy group. The establishment of the structure-activity relationship for the estrogenic properties showed a correlation between the antioxidant and the estrogenic properties. The importance of conformation and hydroxy group positions observed for chalcones, having antioxidant and estrogenic properties, was also observed on MCF-7 cell growth with the same structure-activity relationship. The role of electron and hydrogen transfer in the correlation between these three biological activities was discussed.

Structure-reactivity relationships between fluorescent chromophores and antioxidant activity of grain and sweet sorghum seeds

USDA-ARS?s Scientific Manuscript database

Polyphenolic structures, such as tannins, are the putative cause of a variety of seed functions including bird/insect resistance and antioxidant activity. Structure-reactivity relationships are necessary to understand the influence of polyphenolic chromophore structures on the tannin content and fr...

PREDICTING TOXICOLOGICAL ENDPOINTS OF CHEMICALS USING QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS (QSARS)

EPA Science Inventory

Quantitative structure-activity relationships (QSARs) are being developed to predict the toxicological endpoints for untested chemicals similar in structure to chemicals that have known experimental toxicological data. Based on a very large number of predetermined descriptors, a...

Metal Oxide Nanomaterial QNAR Models: Available Structural Descriptors and Understanding of Toxicity Mechanisms

PubMed Central

Ying, Jiali; Zhang, Ting; Tang, Meng

2015-01-01

Metal oxide nanomaterials are widely used in various areas; however, the divergent published toxicology data makes it difficult to determine whether there is a risk associated with exposure to metal oxide nanomaterials. The application of quantitative structure activity relationship (QSAR) modeling in metal oxide nanomaterials toxicity studies can reduce the need for time-consuming and resource-intensive nanotoxicity tests. The nanostructure and inorganic composition of metal oxide nanomaterials makes this approach different from classical QSAR study; this review lists and classifies some structural descriptors, such as size, cation charge, and band gap energy, in recent metal oxide nanomaterials quantitative nanostructure activity relationship (QNAR) studies and discusses the mechanism of metal oxide nanomaterials toxicity based on these descriptors and traditional nanotoxicity tests. PMID:28347085

What We Know About the Brain Structure-Function Relationship.

PubMed

Batista-García-Ramó, Karla; Fernández-Verdecia, Caridad Ivette

2018-04-18

How the human brain works is still a question, as is its implication with brain architecture: the non-trivial structure–function relationship. The main hypothesis is that the anatomic architecture conditions, but does not determine, the neural network dynamic. The functional connectivity cannot be explained only considering the anatomical substrate. This involves complex and controversial aspects of the neuroscience field and that the methods and methodologies to obtain structural and functional connectivity are not always rigorously applied. The goal of the present article is to discuss about the progress made to elucidate the structure–function relationship of the Central Nervous System, particularly at the brain level, based on results from human and animal studies. The current novel systems and neuroimaging techniques with high resolutive physio-structural capacity have brought about the development of an integral framework of different structural and morphometric tools such as image processing, computational modeling and graph theory. Different laboratories have contributed with in vivo, in vitro and computational/mathematical models to study the intrinsic neural activity patterns based on anatomical connections. We conclude that multi-modal techniques of neuroimaging are required such as an improvement on methodologies for obtaining structural and functional connectivity. Even though simulations of the intrinsic neural activity based on anatomical connectivity can reproduce much of the observed patterns of empirical functional connectivity, future models should be multifactorial to elucidate multi-scale relationships and to infer disorder mechanisms.

Design and preliminary structure-activity relationship of redox-silent semisynthetic tocotrienol analogues as inhibitors for breast cancer proliferation and invasion.

PubMed

Elnagar, Ahmed Y; Wali, Vikram B; Sylvester, Paul W; El Sayed, Khalid A

2010-01-15

Vitamin E (VE) is a generic term that represents a family of compounds composed of various tocopherol and tocotrienol isoforms. Tocotrienols display potent anti-angiogenic and antiproliferative activities. Redox-silent tocotrienol analogues also display potent anticancer activity. The ultimate objective of this study was to develop semisynthetically C-6-modified redox-silent tocotrienol analogues with enhanced antiproliferative and anti-invasive activities as compared to their parent compound. Examples of these are carbamate and ether analogues of alpha-, gamma-, and delta-tocotrienols (1-3). Various aliphatic, olefinic, and aromatic substituents were used. Steric limitation, electrostatic, hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA) properties were varied at this position and the biological activities of these derivatives were tested. Three-dimensional quantitative structure-activity relationship (3D QSAR) studies were performed using Comparative Molecular Field (CoMFA) and Comparative Molecular Similarity Indices Analyses (CoMSIA) to better understand the structural basis for biological activity and guide the future design of more potent VE analogues. Copyright 2009 Elsevier Ltd. All rights reserved.

Forecasting the Environmental Impacts of New Energetic Materials

DTIC Science & Technology

2010-11-30

Quantitative structure- activity relationships for chemical reductions of organic contaminants. Environmental Toxicology and Chemistry 22(8): 1733-1742. QSARs ...activity relationships [ QSARs ]) and the use of these properties to predict the chemical?s fate with multimedia assessment models. SERDP has recently...has several parts, including the prediction of chemical properties (e.g., with quantitative structure-activity relationships [ QSARs ]) and the use of

Multicomplex-based pharmacophore-guided 3D-QSAR studies of N-substituted 2'-(aminoaryl)benzothiazoles as Aurora-A inhibitors.

PubMed

He, Gu; Qiu, Minghua; Li, Rui; Ouyang, Liang; Wu, Fengbo; Song, Xiangrong; Cheng, Li; Xiang, Mingli; Yu, Luoting

2012-06-01

Aurora-A has been known as one of the most important targets for cancer therapy, and some Aurora-A inhibitors have entered clinical trails. In this study, combination of the ligand-based and structure-based methods is used to clarify the essential quantitative structure-activity relationship of known Aurora-A inhibitors, and multicomplex-based pharmacophore-guided method has been suggested to generate a comprehensive pharmacophore of Aurora-A kinase based on a collection of crystal structures of Aurora-A-inhibitor complex. This model has been successfully used to identify the bioactive conformation and align 37 structurally diverse N-substituted 2'-(aminoaryl)benzothiazoles derivatives. The quantitative structure-activity relationship analyses have been performed on these Aurora-A inhibitors based on multicomplex-based pharmacophore-guided alignment. These results may provide important information for further design and virtual screening of novel Aurora-A inhibitors. © 2012 John Wiley & Sons A/S.

Mechanistic Insights into the Specificity of Human Cytosolic Sulfotransferase 2A1 (hSULT2A1) for Hydroxylated Polychlorinated Biphenyls Through the Use of Fluoro-tagged Probes

PubMed Central

Ekuase, E.J.; van ’t Erve, T.J.; Rahaman, A.; Robertson, L.W.; Duffel, M.W.; Luthe, G.

2015-01-01

Determining the relationships between the structures of substrates and inhibitors and their interactions with drug-metabolizing enzymes is of prime importance in predicting the toxic potential of new and legacy xenobiotics. Traditionally, quantitative structure activity relationship (QSAR) studies are performed with many distinct compounds. Based on the chemical properties of the tested compounds, complex relationships can be established so that models can be developed to predict toxicity of novel compounds. In this study, the use of fluorinated analogues as supplemental QSAR compounds was investigated. Substituting fluorine induces changes in electronic and steric properties of the substrate without substantially changing the chemical backbone of the substrate. In vitro assays were performed using purified human cytosolic sulfotransferase hSULT2A1 as a model enzyme. A mono-hydroxylated polychlorinated biphenyl (4-OH PCB 14) and its four possible mono-fluoro analogues were used as test compounds. Remarkable similarities were found between this approach and previously published QSAR studies for hSULT2A1. Both studies implicate the importance of dipole moment and dihedral angle as being important to PCB structure in respect to being substrates for hSULT2A1. We conclude that mono-fluorinated analogues of a target substrate can be a useful tool to study the structure activity relationships for enzyme specificity. PMID:26165989

Synthesis, biological evaluation and structure-activity relationship studies of isoflavene based Mannich bases with potent anti-cancer activity.

PubMed

Chen, Yilin; Cass, Shelley L; Kutty, Samuel K; Yee, Eugene M H; Chan, Daniel S H; Gardner, Christopher R; Vittorio, Orazio; Pasquier, Eddy; Black, David StC; Kumar, Naresh

2015-11-15

Phenoxodiol, an analogue of the isoflavone natural product daidzein, is a potent anti-cancer agent that has been investigated for the treatment of hormone dependent cancers. This molecular scaffold was reacted with different primary amines and secondary amines under different Mannich conditions to yield either benzoxazine or aminomethyl substituted analogues. These processes enabled the generation of a diverse range of analogues that were required for structure-activity relationship (SAR) studies. The resulting Mannich bases exhibited prominent anti-proliferative effects against SHEP neuroblastoma and MDA-MB-231 breast adenocarcinoma cell lines. Further cytotoxicity studies against MRC-5 normal lung fibroblast cells showed that the isoflavene analogues were selective towards cancer cells. Copyright © 2015 Elsevier Ltd. All rights reserved.

Quantitative structure-activity relationship of organosulphur compounds as soybean 15-lipoxygenase inhibitors using CoMFA and CoMSIA.

PubMed

Caballero, Julio; Fernández, Michael; Coll, Deysma

2010-12-01

Three-dimensional quantitative structure-activity relationship studies were carried out on a series of 28 organosulphur compounds as 15-lipoxygenase inhibitors using comparative molecular field analysis and comparative molecular similarity indices analysis. Quantitative information on structure-activity relationships is provided for further rational development and direction of selective synthesis. All models were carried out over a training set including 22 compounds. The best comparative molecular field analysis model only included steric field and had a good Q² = 0.789. Comparative molecular similarity indices analysis overcame the comparative molecular field analysis results: the best comparative molecular similarity indices analysis model also only included steric field and had a Q² = 0.894. In addition, this model predicted adequately the compounds contained in the test set. Furthermore, plots of steric comparative molecular similarity indices analysis field allowed conclusions to be drawn for the choice of suitable inhibitors. In this sense, our model should prove useful in future 15-lipoxygenase inhibitor design studies. © 2010 John Wiley & Sons A/S.

Discovery and Structure-Activity Relationships of the Neoseptins: A New Class of Toll-like Receptor-4 (TLR4) Agonists.

PubMed

Morin, Matthew D; Wang, Ying; Jones, Brian T; Su, Lijing; Surakattula, Murali M R P; Berger, Michael; Huang, Hua; Beutler, Elliot K; Zhang, Hong; Beutler, Bruce; Boger, Dale L

2016-05-26

Herein, we report studies leading to the discovery of the neoseptins and a comprehensive examination of the structure-activity relationships (SARs) of this new class of small-molecule mouse Toll-like receptor 4 (mTLR4) agonists. The compounds in this class, which emerged from screening an α-helix mimetic library, stimulate the immune response, act by a well-defined mechanism (mouse TLR4 agonist), are easy to produce and structurally manipulate, exhibit exquisite SARs, are nontoxic, and elicit improved and qualitatively different responses compared to lipopolysaccharide, even though they share the same receptor.

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.

Quantitative structure-activity relationship study of P2X7 receptor inhibitors using combination of principal component analysis and artificial intelligence methods.

PubMed

Ahmadi, Mehdi; Shahlaei, Mohsen

2015-01-01

P2X7 antagonist activity for a set of 49 molecules of the P2X7 receptor antagonists, derivatives of purine, was modeled with the aid of chemometric and artificial intelligence techniques. The activity of these compounds was estimated by means of combination of principal component analysis (PCA), as a well-known data reduction method, genetic algorithm (GA), as a variable selection technique, and artificial neural network (ANN), as a non-linear modeling method. First, a linear regression, combined with PCA, (principal component regression) was operated to model the structure-activity relationships, and afterwards a combination of PCA and ANN algorithm was employed to accurately predict the biological activity of the P2X7 antagonist. PCA preserves as much of the information as possible contained in the original data set. Seven most important PC's to the studied activity were selected as the inputs of ANN box by an efficient variable selection method, GA. The best computational neural network model was a fully-connected, feed-forward model with 7-7-1 architecture. The developed ANN model was fully evaluated by different validation techniques, including internal and external validation, and chemical applicability domain. All validations showed that the constructed quantitative structure-activity relationship model suggested is robust and satisfactory.

Synthesis and quantitative structure-antifungal activity relationships of clovane derivatives against Botrytis cinerea.

PubMed

Saiz-Urra, Liane; Racero, Juan C; Macías-Sáchez, Antonio J; Hernández-Galán, Rosario; Hanson, James R; Perez-Gonzalez, Maykel; Collado, Isidro G

2009-03-25

Twenty-three clovane derivatives, nine described here for the first time, bearing substituents on carbon C-2, have been synthesized and evaluated for their in vitro antifungal activity against the phytopathogenic fungus Botrytis cinerea. The results showed that compounds 9, 14, 16, and 18 bearing nitrogen atoms in the chain attached at C-2 displayed potent antifungal activity, whereas mercapto derivatives 13, 19, and 22 displayed low activity. The antifungal activity showed a clear structure-activity relationship (SAR) trend, which confirmed the importance of the nature of the C-2 chain on the antifungal activity. On the basis of these observations, the metabolism of compounds 8 and 14 by the fungus B. cinerea, and the metabolism of other clovanes by this fungus, described previously, a pro-drug action mechanism for 2-alkoxyclovane compounds is proposed. Quantitative structure-activity relationship (QSAR) studies were performed to rationalize the results and to suggest further optimization, using a topological sub-structural molecular design (TOPS-MODE) approach. The model displayed good fit and predictive capability, describing 85.5% of the experimental variance, with a standard deviation of 9.502 and yielding high values of cross-validation determination coefficients (q2CV-LOO = 0.784 and q2boot = 0.673). The most significant variables were the spectral moments weighted by bond dipole moment (Dip), hydrophobicity (Hyd), and the combined dipolarity/polarizability Abraham molecular descriptor (Ab-pi2H).

DEVELOPMENT OF STRUCTURE ACTIVITY RELATIONSHIPS FOR ASSESSING ECOLOGICAL RISKS

EPA Science Inventory

In the field of environmental toxicology, structure activity relationships (SARs) have developed as scientifically-credible tools for predicting the effects of chemicals when little or no empirical data are available.

Selective CB2 receptor agonists. Part 2: Structure-activity relationship studies and optimization of proline-based compounds.

PubMed

Riether, Doris; Zindell, Renee; Wu, Lifen; Betageri, Raj; Jenkins, James E; Khor, Someina; Berry, Angela K; Hickey, Eugene R; Ermann, Monika; Albrecht, Claudia; Ceci, Angelo; Gemkow, Mark J; Nagaraja, Nelamangala V; Romig, Helmut; Sauer, Achim; Thomson, David S

2015-02-01

Through a ligand-based pharmacophore model (S)-proline based compounds were identified as potent cannabinoid receptor 2 (CB2) agonists with high selectivity over the cannabinoid receptor 1 (CB1). Structure-activity relationship investigations for this compound class lead to oxo-proline compounds 21 and 22 which combine an impressive CB1 selectivity profile with good pharmacokinetic properties. In a streptozotocin induced diabetic neuropathy model, 22 demonstrated a dose-dependent reversal of mechanical hyperalgesia. Copyright © 2014 Elsevier Ltd. All rights reserved.

Structure-Activity Relationships for the Antifungal Activity of Selective Estrogen Receptor Antagonists Related to Tamoxifen

PubMed Central

Butts, Arielle; Martin, Jennifer A.; DiDone, Louis; Bradley, Erin K.; Mutz, Mitchell; Krysan, Damian J.

2015-01-01

Cryptococcosis is one of the most important invasive fungal infections and is a significant contributor to the mortality associated with HIV/AIDS. As part of our program to repurpose molecules related to the selective estrogen receptor modulator (SERM) tamoxifen as anti-cryptococcal agents, we have explored the structure-activity relationships of a set of structurally diverse SERMs and tamoxifen derivatives. Our data provide the first insights into the structural requirements for the antifungal activity of this scaffold. Three key molecular characteristics affecting anti-cryptococcal activity emerged from our studies: 1) the presence of an alkylamino group tethered to one of the aromatic rings of the triphenylethylene core; 2) an appropriately sized aliphatic substituent at the 2 position of the ethylene moiety; and 3) electronegative substituents on the aromatic rings modestly improved activity. Using a cell-based assay of calmodulin antagonism, we found that the anti-cryptococcal activity of the scaffold correlates with calmodulin inhibition. Finally, we developed a homology model of C. neoformans calmodulin and used it to rationalize the structural basis for the activity of these molecules. Taken together, these data and models provide a basis for the further optimization of this promising anti-cryptococcal scaffold. PMID:26016941

The NMR Structure of Human Obestatin in Membrane-Like Environments: Insights into the Structure-Bioactivity Relationship of Obestatin

PubMed Central

Gurriarán-Rodríguez, Uxía; Mosteiro, Carlos S.; Álvarez-Pérez, Juan C.; Otero-Alén, María; Camiña, Jesús P.; Gallego, Rosalía; García-Caballero, Tomás; Martín-Pastor, Manuel; Casanueva, Felipe F.; Jiménez-Barbero, Jesús; Pazos, Yolanda

2012-01-01

The quest for therapeutic applications of obestatin involves, as a first step, the determination of its 3D solution structure and the relationship between this structure and the biological activity of obestatin. On this basis, we have employed a combination of circular dichroism (CD), nuclear magnetic resonance (NMR) spectroscopy, and modeling techniques to determine the solution structure of human obestatin (1). Other analogues, including human non-amidated obestatin (2) and the fragment peptides (6–23)-obestatin (3), (11–23)-obestatin (4), and (16–23)-obestatin (5) have also been scrutinized. These studies have been performed in a micellar environment to mimic the cell membrane (sodium dodecyl sulfate, SDS). Furthermore, structural-activity relationship studies have been performed by assessing the in vitro proliferative capabilities of these peptides in the human retinal pigmented epithelial cell line ARPE-19 (ERK1/2 and Akt phosphorylation, Ki67 expression, and cellular proliferation). Our findings emphasize the importance of both the primary structure (composition and size) and particular segments of the obestatin molecule that posses significant α-helical characteristics. Additionally, details of a species-specific role for obestatin have also been hypothesized by comparing human and mouse obestatins (1 and 6, respectively) at both the structural and bioactivity levels. PMID:23056203

The NMR structure of human obestatin in membrane-like environments: insights into the structure-bioactivity relationship of obestatin.

PubMed

Alén, Begoña O; Nieto, Lidia; Gurriarán-Rodríguez, Uxía; Mosteiro, Carlos S; Álvarez-Pérez, Juan C; Otero-Alén, María; Camiña, Jesús P; Gallego, Rosalía; García-Caballero, Tomás; Martín-Pastor, Manuel; Casanueva, Felipe F; Jiménez-Barbero, Jesús; Pazos, Yolanda

2012-01-01

The quest for therapeutic applications of obestatin involves, as a first step, the determination of its 3D solution structure and the relationship between this structure and the biological activity of obestatin. On this basis, we have employed a combination of circular dichroism (CD), nuclear magnetic resonance (NMR) spectroscopy, and modeling techniques to determine the solution structure of human obestatin (1). Other analogues, including human non-amidated obestatin (2) and the fragment peptides (6-23)-obestatin (3), (11-23)-obestatin (4), and (16-23)-obestatin (5) have also been scrutinized. These studies have been performed in a micellar environment to mimic the cell membrane (sodium dodecyl sulfate, SDS). Furthermore, structural-activity relationship studies have been performed by assessing the in vitro proliferative capabilities of these peptides in the human retinal pigmented epithelial cell line ARPE-19 (ERK1/2 and Akt phosphorylation, Ki67 expression, and cellular proliferation). Our findings emphasize the importance of both the primary structure (composition and size) and particular segments of the obestatin molecule that posses significant α-helical characteristics. Additionally, details of a species-specific role for obestatin have also been hypothesized by comparing human and mouse obestatins (1 and 6, respectively) at both the structural and bioactivity levels.

Varic acid analogues from fungus as PTP1B inhibitors: Biological evaluation and structure-activity relationships.

PubMed

Sun, Wenlong; Zhuang, Chunlin; Li, Xia; Zhang, Bowei; Lu, Xinhua; Zheng, Zhihui; Dong, Yuesheng

2017-08-01

Protein tyrosine phosphatase 1B (PTP1B) inhibitors as potential therapies for diabetes and obesity have attracted much attention in recent years. Six varic acid analogues were isolated from two strains of fungi and evaluated for PTP1B inhibition activities. The structure-activity relationships were also characterized and predicted by molecular modeling. Further kinetic studies indicated the reversible and competitive inhibition manner of varic acid analogues. Trivaric acid showed insulin-sensitizing effect not only in vitro but also in vivo, representing a promising lead compound for further optimization. Copyright © 2017 Elsevier Ltd. All rights reserved.

Sesterterpenes as tubulin tyrosine ligase inhibitors. First insight of structure-activity relationships and discovery of new lead.

PubMed

Dal Piaz, Fabrizio; Vassallo, Antonio; Lepore, Laura; Tosco, Alessandra; Bader, Ammar; De Tommasi, Nunziatina

2009-06-25

Twenty-four new sesterterpenes, compounds 1-24, were isolated from the aerial parts of Salvia dominica. Their structures were elucidated by 1D and 2D NMR experiments as well as ESIMS analysis and chemical methods. The evaluation of the biological activity of Salvia dominica sesterterpenes by means of a panel of chemical and biological approaches, including chemical proteomics, surface plasmon resonance (SPR) measurements, and biochemical assays were realized. Obtained results showed that 18 out of the 24 sesterterpene lactones isolated from Salvia dominica interact with tubulin-tyrosine ligase (TTL) an enzyme involved in the tyrosination cycle of the C-terminal of tubulin, and inhibit TTL activity in cancer cells. Besides, results of our studies provided an activity/structure relationship that can be used to design effective TTL inhibitors.

The influence of corporate structure and quality improvement activities on outcome improvement in residential care homes.

PubMed

Winters, S; Kool, R B; Klazinga, N S; Huijsman, R

2014-08-01

To examine the impact of corporate structure and quality improvement (QI) activities on improvements in client-reported and professional indicators between 2007 and 2009. A cross-sectional study using organizational survey and indicator multilevel modelling to test relationships between corporate structure, QI activities and performance improvements on indicators. In total, 169 residential care homes for the elderly in the Netherlands. Change between 2007 and 2009 in client-reported and professional indicators. A middle-size corporate structure was associated with QI. The QI activity 'multidisciplinary team meetings' was positively correlated with the indicator 'safety environment' for somatic and psycho-geriatric care. The QI activities 'educational material' and 'direct work instructions' were associated negatively with the indicator 'availability of personnel' for somatic clients, but positively for psycho-geriatric clients. QI activities such as 'health plan activities', 'clinical lessons' and 'financial activities' had no relationship to improved performance. For psycho-geriatric clients mainly organizational QI activities were positively associated with QI. The mediating role of the corporate structure for performing QI activities appeared stronger for the change in client-reported than for professional indicators. This study reveals associations between QI activities and corporate structure and changes in indicator performance. A corporate structure was associated with improvement in client-reported indicators, but less on professional indicators, which assumes a central policy at corporate level with impact on client-reported indicators, in contrast to a more local level approach towards activities that result in QI on professional indicators. Tailoring QI activities at the right managerial level may be important to achieve improvement. © The Author 2014. Published by Oxford University Press in association with the International Society for Quality in Health Care; all rights reserved.

Structure-Activity Relationships of the Human Immunodeficiency Virus Type 1 Maturation Inhibitor PF-46396.

PubMed

Murgatroyd, Christopher; Pirrie, Lisa; Tran, Fanny; Smith, Terry K; Westwood, Nicholas J; Adamson, Catherine S

2016-09-15

HIV-1 maturation inhibitors are a novel class of antiretroviral compounds that consist of two structurally distinct chemical classes: betulinic acid derivatives and the pyridone-based compound PF-46396. It is currently believed that both classes act by similar modes of action to generate aberrant noninfectious particles via inhibition of CA-SP1 cleavage during Gag proteolytic processing. In this study, we utilized a series of novel analogues with decreasing similarity to PF-46396 to determine the chemical groups within PF-46396 that contribute to antiviral activity, Gag binding, and the relationship between these essential properties. A spectrum of antiviral activity (active, intermediate, and inactive) was observed across the analogue series with respect to CA-SP1 cleavage and HIV-1 (NL4-3) replication kinetics in Jurkat T cells. We demonstrate that selected inactive analogues are incorporated into wild-type (WT) immature particles and that one inactive analogue is capable of interfering with PF-46396 inhibition of CA-SP1 cleavage. Mutations that confer PF-46396 resistance can impose a defective phenotype on HIV-1 that can be rescued in a compound-dependent manner. Some inactive analogues retained the capacity to rescue PF-46396-dependent mutants (SP1-A3V, SP1-A3T, and CA-P157S), implying that they can also interact with mutant Gag. The structure-activity relationships observed in this study demonstrate that (i) the tert-butyl group is essential for antiviral activity but is not an absolute requirement for Gag binding, (ii) the trifluoromethyl group is optimal but not essential for antiviral activity, and (iii) the 2-aminoindan group is important for antiviral activity and Gag binding but is not essential, as its replacement is tolerated. Combinations of antiretroviral drugs successfully treat HIV/AIDS patients; however, drug resistance problems make the development of new mechanistic drug classes an ongoing priority. HIV-1 maturation inhibitors are novel as they target the Gag protein, specifically by inhibiting CA-SP1 proteolytic cleavage. The lack of high-resolution structural information of the CA-SP1 target in Gag has hindered our understanding of the inhibitor-binding pocket and maturation inhibitor mode of action. Therefore, we utilized analogues of the maturation inhibitor PF-46396 as chemical tools to determine the chemical components of PF-46396 that contribute to antiviral activity and Gag binding and the relationship between these essential properties. This is the first study to report structure-activity relationships of the maturation inhibitor PF-46396. PF-46396 is chemically distinct from betulinic acid-derived maturation inhibitors; therefore, our data provide a foundation of knowledge that will aid our understanding of how structurally distinct maturation inhibitors act by similar modes of action. Copyright © 2016 Murgatroyd et al.

Chemistry and Structure-Activity Relationships of Psychedelics.

PubMed

Nichols, David E

2018-01-01

This chapter will summarize structure-activity relationships (SAR) that are known for the classic serotonergic hallucinogens (aka psychedelics), focusing on the three chemical types: tryptamines, ergolines, and phenethylamines. In the brain, the serotonin 5-HT 2A receptor plays a key role in regulation of cortical function and cognition, and also appears to be the principal target for hallucinogenic/psychedelic drugs such as LSD. It is one of the most extensively studied of the 14 known types of serotonin receptors. Important structural features will be identified for activity and, where possible, those that the psychedelics have in common will be discussed. Because activation of the 5-HT 2A receptor is the principal mechanism of action for psychedelics, compounds with 5-HT 2A agonist activity generally are quickly discarded by the pharmaceutical industry. Thus, most of the research on psychedelics can be related to activation of 5-HT 2A receptors. Therefore, much of the discussion will include not only clinical or anecdotal studies, but also will consider data from animal models as well as a certain amount of molecular pharmacology where it is known.

[Studies on the structure-activity relationship of retinoids--Hansch analysis and 3D-OSAR studies on specific ligands of retinoid x receptor].

PubMed

Huang, N; Chu, F; Guo, Z

1998-06-01

Retinoids (Vitamin A, its metabolites and synthetic analogues) play important roles in a variety of biological processes, including cellular differentiation, proliferation and apoptosis. The many diverse actions of retinoids attribute to the ability of regulating transcription of different target genes through activation of multiple retinoid nuclear receptors (RAR of RXR). So, retinoids with selective binding ability to specific receptor may not only have improved therapeutic indices, but may also be invaluable for elucidating the molecular mechanism of retinoidal transcriptional activation. Based on the two dimensional and three dimensional quantitative structure-activity relationships of specific ligands of RXR, we carried out mimesis of environment of ligands interacting with their receptor and, to some extent, mapping the topological and physico-chemical characteristics of receptor. The knowledge of the QSAR study will offer detailed molecular information for design, synthesis and biological evaluation in drug research and development.

QSAR study of anthranilic acid sulfonamides as inhibitors of methionine aminopeptidase-2 using LS-SVM and GRNN based on principal components.

PubMed

Shahlaei, Mohsen; Sabet, Razieh; Ziari, Maryam Bahman; Moeinifard, Behzad; Fassihi, Afshin; Karbakhsh, Reza

2010-10-01

Quantitative relationships between molecular structure and methionine aminopeptidase-2 inhibitory activity of a series of cytotoxic anthranilic acid sulfonamide derivatives were discovered. We have demonstrated the detailed application of two efficient nonlinear methods for evaluation of quantitative structure-activity relationships of the studied compounds. Components produced by principal component analysis as input of developed nonlinear models were used. The performance of the developed models namely PC-GRNN and PC-LS-SVM were tested by several validation methods. The resulted PC-LS-SVM model had a high statistical quality (R(2)=0.91 and R(CV)(2)=0.81) for predicting the cytotoxic activity of the compounds. Comparison between predictability of PC-GRNN and PC-LS-SVM indicates that later method has higher ability to predict the activity of the studied molecules. Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.

Antifeedant activity of quassinoids.

PubMed

Leskinen, V; Polonsky, J; Bhatnagar, S

1984-10-01

The antifeedant activity of 13 quassinoids of different structural types has been studied against the Mexican bean beetle (Epilachna varivestis Mulsant) 4th instar larvae and the southern armyworm (Spodoptera eridania Crawer) 5th instar larvae. All quassinoids tested displayed significant activity against the Mexican bean beetle and, thus, do not reveal a simple structure-activity relationship. Five quassinoids were active against the southern armyworm. Interestingly, four of these-bruceantin (I), glaucarubinone (VI), isobruceine A (VIII), and simalikalactone D (XI)-possess the required structural features for antineoplastic activity. The noncytotoxic quassin (X) is an exception; it is active against both pests.

ICI 56,780 Optimization: Structure-Activity Relationship Studies of 7-(2-Phenoxyethoxy)-4(1H)-quinolones with Antimalarial Activity.

PubMed

Maignan, Jordany R; Lichorowic, Cynthia L; Giarrusso, James; Blake, Lynn D; Casandra, Debora; Mutka, Tina S; LaCrue, Alexis N; Burrows, Jeremy N; Willis, Paul A; Kyle, Dennis E; Manetsch, Roman

2016-07-28

Though malaria mortality rates are down 48% globally since 2000, reported occurrences of resistance against current therapeutics threaten to reverse that progress. Recently, antimalarials that were once considered unsuitable therapeutic agents have been revisited to improve physicochemical properties and efficacy required for selection as a drug candidate. One such compound is 4(1H)-quinolone ICI 56,780, which is known to be a causal prophylactic that also displays blood schizonticidal activity against P. berghei. Rapid induction of parasite resistance, however, stalled its further development. We have completed a full structure-activity relationship study on 4(1H)-quinolones, focusing on the reduction of cross-resistance with atovaquone for activity against the clinical isolates W2 and TM90-C2B, as well as the improvement of microsomal stability. These studies revealed several frontrunner compounds with superb in vivo antimalarial activity. The best compounds were found to be curative with all mice surviving a Plasmodium berghei infection after 30 days.

Photoelectron spectra and biological activity of cinnamic acid derivatives revisited

NASA Astrophysics Data System (ADS)

Novak, Igor; Klasinc, Leo; McGlynn, Sean P.

2018-01-01

The electronic structures of several derivatives of cinnamic acid have been studied by UV photoelectron spectroscopy (UPS) and Green's function quantum chemical calculations. The spectra reveal the presence of dimers in the gas phase for p-coumaric and ferulic acids. The electronic structure analysis has been related to the biological properties of these compounds through the analysis of some structure-activity relationships (SAR).

Synthesis of D-glucosamine quaternary ammonium derivatives and evaluation of their antifungal activity together with aminodeoxyglucose derivatives against two wood fungi Coriolus versicolor and Poria placenta: structure-activity relationships.

PubMed

Muhizi, Théoneste; Coma, Véronique; Grelier, Stéphane

2011-03-01

Structure-activity relationships are often reported in scientific studies. These may be employed in searching for new acceptable biocides to use against harmful microorganisms, because the biocides used hitherto encounter various problems, including lack of efficiency, high toxicity and persistence. Nowadays, scientists are trying to find new, environmentally acceptable biocides to replace these earlier biocides. Different compounds from renewable materials have been studied and have shown pronounced antifungal activity against wood fungi. These include aminopolysaccharide derivatives and different quaternary ammonium polymers. A biological study carried out with these products indicated a possible relationship between amino groups and differences in biological activity observed. In this study, an amino group was successively fixed to different carbon atoms of glucose, and glucosamine was also modified by both N-alkylation and quaternisation. The impact of the amino group position on antifungal activity against two wood decay fungi was investigated. The amino group at the anomeric position showed the highest antifungal activity against both Coriolus versicolor Quel. and Poria placenta (Fr.) Cooke. Furthermore, the positive impact of both N-alkylation and quaternisation on the growth of both strains was demonstrated. The anomeric position of the amino group and the N-alkylation and quaternisation of amino sugars considerably increase the antifungal activity of these compounds. Copyright © 2010 Society of Chemical Industry.

Discovery of novel glitazones incorporated with phenylalanine and tyrosine: synthesis, antidiabetic activity and structure-activity relationships.

PubMed

Prashantha Kumar, B R; Baig, Nasir R; Sudhir, Sai; Kar, Koyal; Kiranmai, M; Pankaj, M; Joghee, Nanjan M

2012-12-01

We report a series of new glitazones incorporated with phenylalanine and tyrosine. All the compounds were tested for their in vitro glucose uptake activity using rat-hemidiaphragm, both in presence and absence of insulin. Six of the most active compounds from the in vitro screening were taken forward for their in vivo triglyceride and glucose lowering activity against dexamethazone induced hyperlipidemia and insulin resistance in Wistar rats. The liver samples of rats that received the most active compounds, 23 and 24, in the in vivo studies, were subjected to histopathological examination to assess their short term hepatotoxicity. The investigations on the in vitro glucose uptake, in vivo triglyceride and glucose lowering activity are described here along with the quantitative structure-activity relationships. Copyright © 2012 Elsevier Inc. All rights reserved.

Structure-activity relationships of the antimalarial agent artemisinin. 8. design, synthesis, and CoMFA studies toward the development of artemisinin-based drugs against leishmaniasis and malaria.

PubMed

Avery, Mitchell A; Muraleedharan, Kannoth M; Desai, Prashant V; Bandyopadhyaya, Achintya K; Furtado, Marise M; Tekwani, Babu L

2003-09-25

Artemisinin (1) and its analogues have been well studied for their antimalarial activity. Here we present the antimalarial activity of some novel C-9-modified artemisinin analogues synthesized using artemisitene as the key intermediate. Further, antileishmanial activity of more than 70 artemisinin derivatives against Leishmania donovani promastigotes is described for the first time. A comprehensive structure-activity relationship study using CoMFA is discussed. These analogues exhibited leishmanicidal activity in micromolar concentrations, and the overall activity profile appears to be similar to that against malaria. Substitution at the C-9beta position was shown to improve the activity in both cases. The 10-deoxo derivatives showed better activity compared to the corresponding lactones. In general, compounds with C-9alpha substitution exhibited lower antimalarial as well as antileishmanial activities compared to the corresponding C-9beta analogues. The importance of the peroxide group for the observed activity of these analogues against leishmania was evident from the fact that 1-deoxyartemisinin analogues did not exhibit antileishmanial activity. The study suggests the possibility of developing artemisinin analogues as potential drug candidates against both malaria and leishmaniasis.

Structure–activity relationships study of mTOR kinase inhibition using QSAR and structure-based drug design approaches

PubMed Central

Lakhlili, Wiame; Yasri, Abdelaziz; Ibrahimi, Azeddine

2016-01-01

The discovery of clinically relevant inhibitors of mammalian target of rapamycin (mTOR) for anticancer therapy has proved to be a challenging task. The quantitative structure–activity relationship (QSAR) approach is a very useful and widespread technique for ligand-based drug design, which can be used to identify novel and potent mTOR inhibitors. In this study, we performed two-dimensional QSAR tests, and molecular docking validation tests of a series of mTOR ATP-competitive inhibitors to elucidate their structural properties associated with their activity. The QSAR tests were performed using partial least square method with a correlation coefficient of r2=0.799 and a cross-validation of q2=0.714. The chemical library screening was done by associating ligand-based to structure-based approach using the three-dimensional structure of mTOR developed by homology modeling. We were able to select 22 compounds from two databases as inhibitors of the mTOR kinase active site. We believe that the method and applications highlighted in this study will help future efforts toward the design of selective ATP-competitive inhibitors. PMID:27980424

Structure-activity relationships of lanostane-type triterpenoids from Ganoderma lingzhi as α-glucosidase inhibitors.

PubMed

Fatmawati, Sri; Kondo, Ryuichiro; Shimizu, Kuniyoshi

2013-11-01

A series of lanostane-type triterpenoids, identified as ganoderma alcohols and ganoderma acids, were isolated from the fruiting body of Ganoderma lingzhi. Some of these compounds were confirmed as active inhibitors of the in vitro human recombinant aldose reductase. This paper aims to explain the structural requirement for α-glucosidase inhibition. Our structure-activity studies of ganoderma alcohols showed that the OH substituent at C-3 and the double-bond moiety at C-24 and C-25 are necessary to increase α-glucosidase inhibitory activity. The structure-activity relationships of ganoderma acids revealed that the OH substituent at C-11 is an important feature and that the carboxylic group in the side chain is essential for the recognition of α-glucosidase inhibitory activity. Moreover, the double-bond moiety at C-20 and C-22 in the side chain and the OH substituent at C-3 of ganoderma acids improve α-glucosidase inhibitory activity. These results provide an approach with which to consider the structural requirements of lanostane-type triterpenoids from G. lingzhi. An understanding of these requirements is considered necessary in order to improve a new type of α-glucosidase inhibitor. Copyright © 2013 Elsevier Ltd. All rights reserved.

Structure-activity relationship studies of the lipophilic tail region of sphingosine kinase 2 inhibitors.

PubMed

Congdon, Molly D; Childress, Elizabeth S; Patwardhan, Neeraj N; Gumkowski, James; Morris, Emily A; Kharel, Yugesh; Lynch, Kevin R; Santos, Webster L

2015-11-01

Sphingosine-1-phosphate (S1P) is a ubiquitous, endogenous small molecule that is synthesized by two isoforms of sphingosine kinase (SphK1 and 2). Intervention of the S1P signaling pathway has attracted significant attention because alteration of S1P levels is linked to several disease states including cancer, fibrosis, and sickle cell disease. While intense investigations have focused on developing SphK1 inhibitors, only a limited number of SphK2-selective agents have been reported. Herein, we report our investigations on the structure-activity relationship studies of the lipophilic tail region of SLR080811, a SphK2-selective inhibitor. Our studies demonstrate that the internal phenyl ring is a key structural feature that is essential in the SLR080811 scaffold. Further, we show the dependence of SphK2 activity and selectivity on alkyl tail length, suggesting a larger lipid binding pocket in SphK2 compared to SphK1. Copyright © 2015 Elsevier Ltd. All rights reserved.

Nε-Acryloyllysine Piperazides as Irreversible Inhibitors of Transglutaminase 2: Synthesis, Structure-Activity Relationships, and Pharmacokinetic Profiling.

PubMed

Wodtke, Robert; Hauser, Christoph; Ruiz-Gómez, Gloria; Jäckel, Elisabeth; Bauer, David; Lohse, Martin; Wong, Alan; Pufe, Johanna; Ludwig, Friedrich-Alexander; Fischer, Steffen; Hauser, Sandra; Greif, Dieter; Pisabarro, M Teresa; Pietzsch, Jens; Pietsch, Markus; Löser, Reik

2018-05-24

Transglutaminase 2 (TGase 2)-catalyzed transamidation represents an important post-translational mechanism for protein modification with implications in physiological and pathophysiological conditions, including fibrotic and neoplastic processes. Consequently, this enzyme is considered a promising target for the diagnosis of and therapy for these diseases. In this study, we report on the synthesis and kinetic characterization of N ε -acryloyllysine piperazides as irreversible inhibitors of TGase 2. Systematic structural modifications on 54 new compounds were performed with a major focus on fluorine-bearing substituents due to the potential of such compounds to serve as radiotracer candidates for positron emission tomography. The determined inhibitory activities ranged from 100 to 10 000 M -1 s -1 , which resulted in comprehensive structure-activity relationships. Structure-activity correlations using various substituent parameters accompanied by covalent docking studies provide an advanced understanding of the molecular recognition for this inhibitor class within the active site of TGase 2. Selectivity profiling of selected compounds for other transglutaminases demonstrated an excellent selectivity toward transglutaminase 2. Furthermore, an initial pharmacokinetic profiling of selected inhibitors was performed, including the assessment of potential membrane permeability and liver microsomal stability.

Structure-affinity relationship of the interaction between phenolic acids and their derivatives and β-lactoglobulin and effect on antioxidant activity.

PubMed

Wu, Simin; Zhang, Yunyue; Ren, Fazheng; Qin, Yinghui; Liu, Jiaxin; Liu, Jingwen; Wang, Qingyu; Zhang, Hao

2018-04-15

In this study, 71 phenolic acids and their derivatives were used to investigate the structure-affinity relationship of β-lactoglobulin binding, and the effect of this interaction on antioxidant activity. Based on a fluorescence quenching method, an improved mathematical model was adopted to calculate the binding constants, with a correction for the inner-filter effect. Hydroxylation at the 3-position increased the affinity of the phenolic acids for β-lactoglobulin, while hydroxylation at the 2- or 4-positions had a negative effect. Complete methylation of all hydroxy groups, except at the 3-position, enhanced the binding affinity. Replacing the hydroxy groups with methyl groups at the 2-position also had a positive effect. Hydrogen bonding was one of the binding forces for the interaction. The antioxidant activity of phenolic acid-β-lactoglobulin complexes was higher than that of phenolic acids alone. These findings provide an understanding of the structure-activity relationship of the interaction between β-lactoglobulin and phenolic acids. Copyright © 2017 Elsevier Ltd. All rights reserved.

Nonlinear optical studies and structure-activity relationship of chalcone derivatives with in silico insights

NASA Astrophysics Data System (ADS)

Kar, Swayamsiddha; Adithya, K. S.; Shankar, Pruthvik; Jagadeesh Babu, N.; Srivastava, Sailesh; Nageswara Rao, G.

2017-07-01

Nine chalcones were prepared via Claisen-Schmidt condensation, and characterized by UV-vis, IR, 1H NMR, 13C NMR and mass spectrometry. One of the representative member 4-NDM-TC has been studied via single crystal XRD and the TGA/DTA technique. SHG efficiency and NLO susceptibilities of the chalcones have been evaluated by the Kurtz and Perry method and Degenerate Four Wave Mixing techniques respectively. 3-Cl-4‧-HC was noted to possess SHG efficiency 1.37 times that of urea while 4-NDM-TC returned the highest third order NLO susceptibilities with respect to CS2. In silico studies help evaluate various physical parameters, in correlating the observed activities. In conclusion, the structure-activity relationship was derived based on the in silico and experimental results for the third order NLO susceptibilities.

Relationship between haemolytic and adjuvant activity and structure of protopanaxadiol-type saponins from the roots of Panax notoginseng.

PubMed

Sun, Hong-Xiang; Qin, Feng; Ye, Yi-Ping

2005-12-01

Four protopanaxadiol-type saponins (PDS), ginsenosides-Rb(1), -Rd, notoginsenosides-K, -R(4) isolated from the roots of Panax notoginseng were evaluated for their haemolytic activities and adjuvant potentials on the cellular and humoral immune responses of ICR mice against ovalbumin (OVA). The effect of the substitution pattern of these PDS on their biological activities was investigated and structure-activity relationships were established. Among four PDS, the ranking of the haemolytic activity was K>R(4)>Rb(1)>Rd (P<0.01 or <0.001). Rd, Rb(1), and K could significantly enhance mitogen- and OVA-induced splenocyte proliferation in the OVA-immunized mice (P<0.001), with the order in terms of stimulation index being Rd>Rb(1)>K>R(4). OVA-specific IgG, IgG1, IgG2a and IgG2b antibody levels in the OVA-immunized mice were significantly enhanced by four PDS. Adjuvant potentials of Rd on antibody responses were higher than those of other three PDS. Meanwhile, Rd also significantly enhanced the production of the Th1 and Th2 cytokines in OVA-immunized mice (P<0.05 or <0.01). The structure-activity relationship studies suggested that the length of sugar side chains at position C-20 and the linkage of glucose moiety at position C-3 of protopanaxadiol could affect the haemolytic and adjuvant activities of PDS. The information about this structure/function relationship might be useful for developing semisynthetic tetracyclic triterpenoid saponin derivatives with immunological adjuvant activity, as well as a reference to the distribution of the functional groups composing the saponin molecule.

Cationic lipids: molecular structure/ transfection activity relationships and interactions with biomembranes.

PubMed

Koynova, Rumiana; Tenchov, Boris

2010-01-01

Abstract Synthetic cationic lipids, which form complexes (lipoplexes) with polyanionic DNA, are presently the most widely used constituents of nonviral gene carriers. A large number of cationic amphiphiles have been synthesized and tested in transfection studies. However, due to the complexity of the transfection pathway, no general schemes have emerged for correlating the cationic lipid chemistry with their transfection efficacy and the approaches for optimizing their molecular structures are still largely empirical. Here we summarize data on the relationships between transfection activity and cationic lipid molecular structure and demonstrate that the transfection activity depends in a systematic way on the lipid hydrocarbon chain structure. A number of examples, including a large series of cationic phosphatidylcholine derivatives, show that optimum transfection is displayed by lipids with chain length of approximately 14 carbon atoms and that the transfection efficiency strongly increases with increase of chain unsaturation, specifically upon replacement of saturated with monounsaturated chains.

Flavonoid interactions during digestion, absorption, distribution and metabolism: a sequential structure-activity/property relationship-based approach in the study of bioavailability and bioactivity.

PubMed

Gonzales, Gerard Bryan; Smagghe, Guy; Grootaert, Charlotte; Zotti, Moises; Raes, Katleen; Van Camp, John

2015-05-01

Flavonoids are a group of polyphenols that provide health-promoting benefits upon consumption. However, poor bioavailability has been a major hurdle in their use as drugs or nutraceuticals. Low bioavailability has been associated with flavonoid interactions at various stages of the digestion, absorption and distribution process, which is strongly affected by their molecular structure. In this review, we use structure-activity/property relationship to discuss various flavonoid interactions with food matrices, digestive enzymes, intestinal transporters and blood proteins. This approach reveals specific bioactive properties of flavonoids in the gastrointestinal tract as well as various barriers for their bioavailability. In the last part of this review, we use these insights to determine the effect of different structural characteristics on the overall bioavailability of flavonoids. Such information is crucial when flavonoid or flavonoid derivatives are used as active ingredients in foods or drugs.

Structure-Thermodynamics-Antioxidant Activity Relationships of Selected Natural Phenolic Acids and Derivatives: An Experimental and Theoretical Evaluation

PubMed Central

Zheng, Jie; Liang, Guizhao

2015-01-01

Phenolic acids and derivatives have potential biological functions, however, little is known about the structure-activity relationships and the underlying action mechanisms of these phenolic acids to date. Herein we investigate the structure-thermodynamics-antioxidant relationships of 20 natural phenolic acids and derivatives using DPPH• scavenging assay, density functional theory calculations at the B3LYP/6-311++G(d,p) levels of theory, and quantitative structure-activity relationship (QSAR) modeling. Three main working mechanisms (HAT, SETPT and SPLET) are explored in four micro-environments (gas-phase, benzene, water and ethanol). Computed thermodynamics parameters (BDE, IP, PDE, PA and ETE) are compared with the experimental radical scavenging activities against DPPH•. Available theoretical and experimental investigations have demonstrated that the extended delocalization and intra-molecular hydrogen bonds are the two main contributions to the stability of the radicals. The C = O or C = C in COOH, COOR, C = CCOOH and C = CCOOR groups, and orthodiphenolic functionalities are shown to favorably stabilize the specific radical species to enhance the radical scavenging activities, while the presence of the single OH in the ortho position of the COOH group disfavors the activities. HAT is the thermodynamically preferred mechanism in the gas phase and benzene, whereas SPLET in water and ethanol. Furthermore, our QSAR models robustly represent the structure-activity relationships of these explored compounds in polar media. PMID:25803685

Structure-thermodynamics-antioxidant activity relationships of selected natural phenolic acids and derivatives: an experimental and theoretical evaluation.

PubMed

Chen, Yuzhen; Xiao, Huizhi; Zheng, Jie; Liang, Guizhao

2015-01-01

Phenolic acids and derivatives have potential biological functions, however, little is known about the structure-activity relationships and the underlying action mechanisms of these phenolic acids to date. Herein we investigate the structure-thermodynamics-antioxidant relationships of 20 natural phenolic acids and derivatives using DPPH• scavenging assay, density functional theory calculations at the B3LYP/6-311++G(d,p) levels of theory, and quantitative structure-activity relationship (QSAR) modeling. Three main working mechanisms (HAT, SETPT and SPLET) are explored in four micro-environments (gas-phase, benzene, water and ethanol). Computed thermodynamics parameters (BDE, IP, PDE, PA and ETE) are compared with the experimental radical scavenging activities against DPPH•. Available theoretical and experimental investigations have demonstrated that the extended delocalization and intra-molecular hydrogen bonds are the two main contributions to the stability of the radicals. The C = O or C = C in COOH, COOR, C = CCOOH and C = CCOOR groups, and orthodiphenolic functionalities are shown to favorably stabilize the specific radical species to enhance the radical scavenging activities, while the presence of the single OH in the ortho position of the COOH group disfavors the activities. HAT is the thermodynamically preferred mechanism in the gas phase and benzene, whereas SPLET in water and ethanol. Furthermore, our QSAR models robustly represent the structure-activity relationships of these explored compounds in polar media.

Relating Anaerobic Digestion Microbial Community and Process Function.

PubMed

Venkiteshwaran, Kaushik; Bocher, Benjamin; Maki, James; Zitomer, Daniel

2015-01-01

Anaerobic digestion (AD) involves a consortium of microorganisms that convert substrates into biogas containing methane for renewable energy. The technology has suffered from the perception of being periodically unstable due to limited understanding of the relationship between microbial community structure and function. The emphasis of this review is to describe microbial communities in digesters and quantitative and qualitative relationships between community structure and digester function. Progress has been made in the past few decades to identify key microorganisms influencing AD. Yet, more work is required to realize robust, quantitative relationships between microbial community structure and functions such as methane production rate and resilience after perturbations. Other promising areas of research for improved AD may include methods to increase/control (1) hydrolysis rate, (2) direct interspecies electron transfer to methanogens, (3) community structure-function relationships of methanogens, (4) methanogenesis via acetate oxidation, and (5) bioaugmentation to study community-activity relationships or improve engineered bioprocesses.

Cytotoxic lanostane-type triterpenoids from the fruiting bodies of Ganoderma lucidum and their structure-activity relationships.

PubMed

Chen, Shaodan; Li, Xiangmin; Yong, Tianqiao; Wang, Zhanggen; Su, Jiyan; Jiao, Chunwei; Xie, Yizhen; Yang, Burton B

2017-02-07

We conducted a study of Ganoderma lucidum metabolites and isolated 35 lanostane-type triterpenoids, including 5 new ganoderols (1-5). By spectroscopy, we compared the structures of these compounds with known related compounds in this group. All of the isolated compounds were assayed for their effect against the human breast carcinoma cell line MDA-MB-231 and hepatocellular carcinoma cell line HepG2. Corresponding three-dimensional quantitative structure-activity relationship (3D-QSAR) models were built and analyzed using Discovery Studio. These results provide further evidence for anti-cancer constituents within Ganoderma lucidum, and may provide a theoretical foundation for designing novel therapeutic compounds.

Rapid identification of Keap1-Nrf2 small-molecule inhibitors through structure-based virtual screening and hit-based substructure search.

PubMed

Zhuang, Chunlin; Narayanapillai, Sreekanth; Zhang, Wannian; Sham, Yuk Yin; Xing, Chengguo

2014-02-13

In this study, rapid structure-based virtual screening and hit-based substructure search were utilized to identify small molecules that disrupt the interaction of Keap1-Nrf2. Special emphasis was placed toward maximizing the exploration of chemical diversity of the initial hits while economically establishing informative structure-activity relationship (SAR) of novel scaffolds. Our most potent noncovalent inhibitor exhibits three times improved cellular activation in Nrf2 activation than the most active noncovalent Keap1 inhibitor known to date.

Synthesis, quantitative structure-property relationship study of novel fluorescence active 2-pyrazolines and application.

PubMed

Girgis, Adel S; Basta, Altaf H; El-Saied, Houssni; Mohamed, Mohamed A; Bedair, Ahmad H; Salim, Ahmad S

2018-03-01

A variety of fluorescence-active fluorinated pyrazolines 13-33 was synthesized in good yields through cyclocondensation reaction of propenones 1-9 with aryl hydrazines 10-12 . Some of the synthesized compounds provided promising fluorescence properties with quantum yield ( Φ ) higher than that of quinine sulfate (standard reference). Quantitative structure-property relationship studies were undertaken supporting the exhibited fluorescence properties and estimating the parameters governing properties. Five synthesized fluorescence-active pyrazolines ( 13 , 15 , 18 , 19 and 23 ) with variable Φ were selected for treating two types of paper sheets (Fabriano and Bible paper). These investigated fluorescence compounds, especially compounds 19 and 23 , provide improvements in strength properties of paper sheets. Based on the observed performance they can be used as markers in security documents.

Synthesis, quantitative structure-property relationship study of novel fluorescence active 2-pyrazolines and application

NASA Astrophysics Data System (ADS)

Girgis, Adel S.; Basta, Altaf H.; El-Saied, Houssni; Mohamed, Mohamed A.; Bedair, Ahmad H.; Salim, Ahmad S.

2018-03-01

A variety of fluorescence-active fluorinated pyrazolines 13-33 was synthesized in good yields through cyclocondensation reaction of propenones 1-9 with aryl hydrazines 10-12. Some of the synthesized compounds provided promising fluorescence properties with quantum yield (Φ) higher than that of quinine sulfate (standard reference). Quantitative structure-property relationship studies were undertaken supporting the exhibited fluorescence properties and estimating the parameters governing properties. Five synthesized fluorescence-active pyrazolines (13, 15, 18, 19 and 23) with variable Φ were selected for treating two types of paper sheets (Fabriano and Bible paper). These investigated fluorescence compounds, especially compounds 19 and 23, provide improvements in strength properties of paper sheets. Based on the observed performance they can be used as markers in security documents.

Structure Diversity, Synthesis, and Biological Activity of Cyathane Diterpenoids in Higher Fungi.

PubMed

Tang, Hao-Yu; Yin, Xia; Zhang, Cheng-Chen; Jia, Qian; Gao, Jin-Ming

2015-01-01

Cyathane diterpenoids, occurring exclusively in higher basidiomycete (mushrooms), represent a structurally diverse class of natural products based on a characteristic 5-6-7 tricyclic carbon scaffold, including 105 members reported to date. These compounds show a diverse range of biological activities, such as antimicrobial, anti-MRSA, agonistic toward the kappa-opioid receptor, antiinflammatory, anti-proliferative and nerve growth factor (NGF)-like properties. The present review focuses on the structure diversity, structure elucidation and biological studies of these compounds, including mechanisms of actions and structure-activity relationships (SARs). In addition, new progress in chemical synthesis of cyathane diterpenoids is discussed.

Design, synthesis and preliminary structure-activity relationship investigation of nitrogen-containing chalcone derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors: a further study based on Flavokawain B Mannich base derivatives.

PubMed

Liu, Haoran; Fan, Haoqun; Gao, Xiaohui; Huang, Xueqing; Liu, Xianjun; Liu, Linbo; Zhou, Chao; Tang, Jingjing; Wang, Qiuan; Liu, Wukun

2016-08-01

In order to study the structure-activity relationship of Flavokawain B Mannich-based derivatives as acetylcholinesterase (AChE) inhibitors in our recent investigation, 20 new nitrogen-containing chalcone derivatives (4 a-8d) were designed, synthesized, and evaluated for AChE inhibitory activity in vitro. The results suggested that amino alkyl side chain of chalcone dramatically influenced the inhibitory activity against AChE. Among them, compound 6c revealed the strongest AChE inhibitory activity (IC50 value: 0.85 μmol/L) and the highest selectivity against AChE over BuChE (ratio: 35.79). Enzyme kinetic study showed that the inhibition mechanism of compound 6c against AChE was a mixed-type inhibition. The molecular docking assay showed that this compound can both bind with the catalytic site and the peripheral site of AChE.

Organizing for the Third Mission: Structural Conditions for Outreach and Relevance at Two Swedish HEIs

ERIC Educational Resources Information Center

Hellstrom, Tomas; Jacob, Merle; Wigren-Kristoferson, Caroline

2013-01-01

The authors investigate how Third Mission activities at universities, such as the outreach and technology transfer functions, are anchored in organizational structures and practices, and discuss the implications of this relationship for the success of the activities. They draw on case studies of two Swedish university colleges to illustrate the…

Identification of Lilial as a fragrance sensitizer in a perfume by bioassay-guided chemical fractionation and structure-activity relationships.

PubMed

Arnau, E G; Andersen, K E; Bruze, M; Frosch, P J; Johansen, J D; Menné, T; Rastogi, S C; White, I R; Lepoittevin, J P

2000-12-01

Fragrance materials are among the most common causes of allergic contact dermatitis. The aim of this study was to identify in a perfume fragrance allergens not included in the fragrance mix, by use of bioassay-guided chemical fractionation and chemical analysis/structure-activity relationships (SARs). The basis for the investigation was a 45-year-old woman allergic to her own perfume. She had a negative patch test to the fragrance mix and agreed to participate in the study. Chemical fractionation of the perfume concentrate was used for repeated patch testing and/or repeated open application test on the pre-sensitized patient. The chemical composition of the fractions giving a positive patch-test response and repeated open application test reactions was obtained by gas chromatography-mass spectrometry. From the compounds identified, those that contained a "structural alert" in their chemical structure, indicating an ability to modify skin proteins and thus behave as a skin sensitizer, were tested on the patient. The patient reacted positively to the synthetic fragrance p-t-butyl-alpha-methylhydrocinnamic aldehyde (Lilial), a widely used fragrance compound not present in the fragrance mix. The combination of bioassay-guided chemical fractionation and chemical analysis/structure-activity relationships seems to be a valuable tool for the investigation of contact allergy to fragrance materials.

Arylazolyl(azinyl)thioacetanilides. Part 16: Structure-based bioisosterism design, synthesis and biological evaluation of novel pyrimidinylthioacetanilides as potent HIV-1 inhibitors.

PubMed

Li, Xiao; Lu, Xueyi; Chen, Wenmin; Liu, Huiqing; Zhan, Peng; Pannecouque, Christophe; Balzarini, Jan; De Clercq, Erik; Liu, Xinyong

2014-10-01

A series of novel pyrimidinylthioacetanilides were designed, synthesized, and evaluated for their biological activity as potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Most of the tested compounds were proved to be effective in inhibiting HIV-1 (IIIB) replication with EC50 ranging from 0.15 μM to 24.2 μM, thereinto compound 15 was the most active lead with favorable inhibitory activity against HIV-1 (IIIB) (EC50=0.15 μM, SI=684). Besides, compound 6 displayed moderate inhibition against the double-mutated HIV-1 strain (K103N/Y181C) (EC50=3.9 μM). Preliminary structure-activity relationships (SARs), structure-cytotoxicity relationships (SCRs) data, and molecular modeling studies were discussed as well, which may provide valuable insights for further optimizations. Copyright © 2014 Elsevier Ltd. All rights reserved.

The structure-activity relationship of inhibitors of serotonin uptake and receptor binding

NASA Astrophysics Data System (ADS)

Hansch, Corwin; Caldwell, Jonathan

1991-10-01

An analysis of five different datasets of inhibitors of serotonin uptake has yielded quantitative structure/ activity relationships (QSARs) which delineate the role of steric and hydrophobic properties essential for inhibition by phenylethylamine-type analogues.

Essential Set of Molecular Descriptors for ADME Prediction in Drug and Environmental Chemical Space

EPA Science Inventory

Historically, the disciplines of pharmacology and toxicology have embraced quantitative structure-activity relationships (QSAR) and quantitative structure-property relationships (QSPR) to predict ADME properties or biological activities of untested chemicals. The question arises ...

In vitro and in vivo structure and activity relationship analysis of polymethoxylated flavonoids: identifying sinensetin as a novel antiangiogenesis agent.

PubMed

Lam, In Kei; Alex, Deepa; Wang, You-Hua; Liu, Ping; Liu, Ai-Lin; Du, Guan-Hua; Lee, Simon Ming Yuen

2012-06-01

Polymethoxylated flavonoids are present in citrus fruit in a range of chemical structures and abundance. These compounds have potential for anticarcinogenesis, antitumor, and cardiovascular protective activity, but the effect on angiogenesis has not been well studied. Human umbilical vein endothelial cells (HUVECs) in vitro and zebrafish (Danio rerio) in vivo models were used to screen and identify the antiangiogenesis activity of seven polymethoxylated flavonoids; namely, hesperetin, naringin, neohesperidin, nobiletin, scutellarein, scutellarein tetramethylether, and sinensetin. Five, excluding naringin and neohesperidin, showed different degrees of potency of antiangiogenesis activity. Sinensetin, which had the most potent antiangiogenesis activity and the lowest toxicity, inhibited angiogenesis by inducing cell cycle arrest in the G0/G1 phase in HUVEC culture and downregulating the mRNA expressions of angiogenesis genes flt1, kdrl, and hras in zebrafish. The in vivo structure-activity relationship (SAR) analysis indicated that a flavonoid with a methoxylated group at the C3' position offers a stronger antiangiogenesis activity, whereas the absence of a methoxylated group at the C8 position offers lower lethal toxicity in addition to enhancing the antiangiogenesis activity. This study provides new insight into how modification of the chemical structure of polymethoxylated flavonoids affects this newly identified antiangiogenesis activity. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis, antibacterial and anti-MRSA activity, in vivo toxicity and a structure-activity relationship study of a quinoline thiourea.

PubMed

Dolan, Niamh; Gavin, Declan P; Eshwika, Ahmed; Kavanagh, Kevin; McGinley, John; Stephens, John C

2016-01-15

We report the synthesis, antibacterial evaluation of a series of thiourea-containing compounds. 1-(3,5-Bis(trifluoromethyl)phenyl)-3-((S)-(6-methoxyquinolin-4-yl)-((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)thiourea 5, was the most active against a range of Gram-positive and Gram-negative bacteria, and exhibited bacteriostatic activity against methicillin resistant Staphylococcus aureus (MRSA) comparable to that of the well-known antibacterial agent vancomycin. Quinoline thiourea 5 was subjected to a detailed structure-activity relationship study, with 5 and its derivatives evaluated for their bacteriostatic activity against both Gram-negative and Gram-positive bacteria. A number of structural features important for the overall activity of quinoline thiourea 5 have been identified. A selection of compounds, including 5, was also evaluated for their in vivo toxicity using the larvae of the Greater wax moth, Galleria mellonella. Compound 5, and a number of derivatives, were found to be non-toxic to the larvae of Galleria mellonella. A new class of antibiotic can result from the further development of this family of compounds. Copyright © 2015 Elsevier Ltd. All rights reserved.

The relationship between physical activity, meaning in life, and subjective vitality in community-dwelling older adults.

PubMed

Ju, Haewon

2017-11-01

The present study examined the potential contribution of meaning in life to the relationship between physical activity and subjective vitality in older adults. Two-hundred and fifty community-dwelling elders completed the instruments assessing physical activity, meaning in life, and subjective vitality. Results from structural equation modeling indicated that physical activity was positively associated with both meaning in life and subjective vitality. Further, the relationship between physical activity and vitality was partially mediated by meaning in life. Although previous studies have consistently found a positive impact of physical activity on vitality, the current study suggested that it is more productive to focus not only on physical activity, but also on meaning in life, in order to vitalize elders. Further, a focus on meaning in life can be a productive way to continue to vitalize older adults who are unable to engage in regular physical activity. Copyright © 2017 Elsevier B.V. All rights reserved.

Structure-Activity Relationships Based on 3D-QSAR CoMFA/CoMSIA and Design of Aryloxypropanol-Amine Agonists with Selectivity for the Human β3-Adrenergic Receptor and Anti-Obesity and Anti-Diabetic Profiles.

PubMed

Lorca, Marcos; Morales-Verdejo, Cesar; Vásquez-Velásquez, David; Andrades-Lagos, Juan; Campanini-Salinas, Javier; Soto-Delgado, Jorge; Recabarren-Gajardo, Gonzalo; Mella, Jaime

2018-05-16

The wide tissue distribution of the adrenergic β3 receptor makes it a potential target for the treatment of multiple pathologies such as diabetes, obesity, depression, overactive bladder (OAB), and cancer. Currently, there is only one drug on the market, mirabegron, approved for the treatment of OAB. In the present study, we have carried out an extensive structure-activity relationship analysis of a series of 41 aryloxypropanolamine compounds based on three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques. This is the first combined comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) study in a series of selective aryloxypropanolamines displaying anti-diabetes and anti-obesity pharmacological profiles. The best CoMFA and CoMSIA models presented values of r ² ncv = 0.993 and 0.984 and values of r ² test = 0.865 and 0.918, respectively. The results obtained were subjected to extensive external validation ( q ², r ², r ² m , etc.) and a final series of compounds was designed and their biological activity was predicted (best pEC 50 = 8.561).

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.

Structure-activity relationships of 3-O-β-chacotriosyl oleanane-type triterpenoids as potential H5N1 entry inhibitors.

PubMed

Song, Gaopeng; Shen, Xintian; Li, Sumei; Li, Yibin; Si, Hongzong; Fan, Jihong; Li, Junhua; Gao, Erqiang; Liu, Shuwen

2016-08-25

A series of 3-O-β-chacotriosyl oleanolic acid analogs have been designed, synthesized and evaluated as H5N1 entry inhibitors based on a small molecule inhibitor saponin 1 previously discovered by us. Detailed structure-activity relationships (SARs) studies on the aglycone of compound 1 indicated that the subtle modification of oleanolic acid as an aglycon has key influences on the antiviral activity. These results suggested that either the introduction of a disubstituted amide structure at the 17-COOH of OA or alteration of the C-3 configuration of OA from 3β-to 3α-forms can significantly improve the selective index while maintaining their antiviral activities in vitro. Compound 8 was selected for further mechanistic study because of its distinguished inhibition activity and good selective index. Molecular simulation study and surface plasmon resonance analysis confirmed that compound 8 stabilized HA2 subunit of hemagglutinin (HA) by binding with amino acid residues LYS-26, ASN-53, ASN-27 and ASN-50, therefore may prevent HA from conformational rearranging, which is a critical step for viral entry. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Structure-Activity Relationships of Nitro-Substituted Aroylhydrazone Iron Chelators with Antioxidant and Antiproliferative Activities.

PubMed

Hrušková, Kateřina; Potůčková, Eliška; Opálka, Lukáš; Hergeselová, Tereza; Hašková, Pavlína; Kovaříková, Petra; Šimůnek, Tomáš; Vávrová, Kateřina

2018-05-23

Aroylhydrazone iron chelators such as salicylaldehyde isonicotinoyl hydrazone (SIH) protect various cells against oxidative injury and display antineoplastic activities. Previous studies have shown that a nitro-substituted hydrazone, namely, NHAPI, displayed markedly improved plasma stability, selective antitumor activity, and moderate antioxidant properties. In this study, we prepared four series of novel NHAPI derivatives and explored their iron chelation activities, anti- or pro-oxidant effects, protection against model oxidative injury in the H9c2 cell line derived from rat embryonic cardiac myoblasts, cytotoxicities to the corresponding noncancerous H9c2 cells, and antiproliferative activities against the MCF-7 human breast adenocarcinoma and HL-60 human promyelocytic leukemia cell lines. Nitro substitution had both negative and positive effects on the examined properties, and we identified new structure-activity relationships. Naphthyl and biphenyl derivatives showed selective antiproliferative action, particularly in the breast adenocarcinoma MCF-7 cell line, where they exceeded the selectivity of the parent compound NHAPI. Of particular interest is a compound prepared from 2-hydroxy-5-methyl-3-nitroacetophenone and biphenyl-4-carbohydrazide, which protected cardiomyoblasts against oxidative injury at 1.8 ± 1.2 μM with 24-fold higher selectivity than SIH. These compounds will serve as leads for further structural optimization and mechanistic studies.

Anti-AIDS agents 81. Design, synthesis, and structure-activity relationship study of betulinic acid and moronic acid derivatives as potent HIV maturation inhibitors.

PubMed

Qian, Keduo; Kuo, Reen-Yun; Chen, Chin-Ho; Huang, Li; Morris-Natschke, Susan L; Lee, Kuo-Hsiung

2010-04-22

In our continuing study of triterpene derivatives as potent anti-HIV agents, different C-3 conformationally restricted betulinic acid (BA, 1) derivatives were designed and synthesized in order to explore the conformational space of the C-3 pharmacophore. 3-O-Monomethylsuccinyl-betulinic acid (MSB) analogues were also designed to better understand the contribution of the C-3' dimethyl group of bevirimat (2), the first-in-class HIV maturation inhibitor, which is currently in phase IIb clinical trials. In addition, another triterpene skeleton, moronic acid (MA, 3), was also employed to study the influence of the backbone and the C-3 modification toward the anti-HIV activity of this compound class. This study enabled us to better understand the structure-activity relationships (SAR) of triterpene-derived anti-HIV agents and led to the design and synthesis of compound 12 (EC(50): 0.0006 microM), which displayed slightly better activity than 2 as a HIV-1 maturation inhibitor.

Antimalarial benzoheterocyclic 4-aminoquinolines: Structure-activity relationship, in vivo evaluation, mechanistic and bioactivation studies.

PubMed

Ongarora, Dennis S B; Strydom, Natasha; Wicht, Kathryn; Njoroge, Mathew; Wiesner, Lubbe; Egan, Timothy J; Wittlin, Sergio; Jurva, Ulrik; Masimirembwa, Collen M; Chibale, Kelly

2015-09-01

A novel class of benzoheterocyclic analogues of amodiaquine designed to avoid toxic reactive metabolite formation was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant) and NF54 (sensitive) strains of the malaria parasite Plasmodium falciparum. Structure-activity relationship studies led to the identification of highly promising analogues, the most potent of which had IC50s in the nanomolar range against both strains. The compounds further demonstrated good in vitro microsomal metabolic stability while those subjected to in vivo pharmacokinetic studies had desirable pharmacokinetic profiles. In vivo antimalarial efficacy in Plasmodium berghei infected mice was evaluated for four compounds, all of which showed good activity following oral administration. In particular, compound 19 completely cured treated mice at a low multiple dose of 4×10mg/kg. Mechanistic and bioactivation studies suggest hemozoin formation inhibition and a low likelihood of forming quinone-imine reactive metabolites, respectively. Copyright © 2015 Elsevier Ltd. All rights reserved.

Dimensional Model for Estimating Factors influencing Childhood Obesity: Path Analysis Based Modeling

PubMed Central

Kheirollahpour, Maryam; Shohaimi, Shamarina

2014-01-01

The main objective of this study is to identify and develop a comprehensive model which estimates and evaluates the overall relations among the factors that lead to weight gain in children by using structural equation modeling. The proposed models in this study explore the connection among the socioeconomic status of the family, parental feeding practice, and physical activity. Six structural models were tested to identify the direct and indirect relationship between the socioeconomic status and parental feeding practice general level of physical activity, and weight status of children. Finally, a comprehensive model was devised to show how these factors relate to each other as well as to the body mass index (BMI) of the children simultaneously. Concerning the methodology of the current study, confirmatory factor analysis (CFA) was applied to reveal the hidden (secondary) effect of socioeconomic factors on feeding practice and ultimately on the weight status of the children and also to determine the degree of model fit. The comprehensive structural model tested in this study suggested that there are significant direct and indirect relationships among variables of interest. Moreover, the results suggest that parental feeding practice and physical activity are mediators in the structural model. PMID:25097878

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.

Using Theoretical Descriptions in Structure Activity Relations. 3. Electronic Descriptors

DTIC Science & Technology

1988-08-01

Activity Relationships (QSAR) have been used successfully in the past to develop predictive equations for several biological and physical properties...Linear Free Energy Relationships (,FF.3) and is based on work by Hammet in which he derived electronic descriptors for the dissociation of substituted...structure of a compound and its activity in a system. Several different structural descriptors have been used in QSAR equations . These range from

Connectome Signatures of Neurocognitive Abnormalities in Euthymic Bipolar I Disorder

PubMed Central

Ajilore, Olusola; Vizueta, Nathalie; Walshaw, Patricia; Zhan, Liang; Leow, Alex; Altshuler, Lori L.

2015-01-01

Objectives Connectomics have allowed researchers to study integrative patterns of neural connectivity in humans. Yet, it is unclear how connectomics may elucidate structure-function relationships in bipolar I disorder (BPI). Expanding on our previous structural connectome study, here we used an overlapping sample with additional psychometric and fMRI data to relate structural connectome properties to both fMRI signals and cognitive performance. Methods 42 subjects completed a neuropsychological (NP) battery covering domains of processing speed, verbal memory, working memory, and cognitive flexibility. 32 subjects also had fMRI data performing a Go/NoGo task. Results Bipolar participants had lower NP performance across all domains, but only working memory reached statistical significance. In BPI participants, processing speed was significantly associated with both white matter integrity (WMI) in the corpus callosum and interhemispheric network integration. Mediation models further revealed that the relationship between interhemispheric integration and processing speed was mediated by WMI, and processing speed mediated the relationship between WMI and working memory. Bipolar subjects had significantly decreased BA47 activation during NoGo vs. Go. Significant predictors of BA47 fMRI activations during the Go/NoGo task were its nodal path length (left hemisphere) and its nodal clustering coefficient (right hemisphere). Conclusions This study suggests that structural connectome changes underlie abnormalities in fMRI activation and cognitive performance in euthymic BPI subjects. Results support that BA47 structural connectome changes may be a trait marker for BPI. Future studies are needed to determine if these “connectome signatures” may also confer a biological risk and/or serve as predictors of relapse. PMID:26228398

MOLECULAR INTERACTION POTENTIALS FOR THE DEVELOPMENT OF STRUCTURE-ACTIVITY RELATIONSHIPS

EPA Science Inventory

Abstract
One reasonable approach to the analysis of the relationships between molecular structure and toxic activity is through the investigation of the forces and intermolecular interactions responsible for chemical toxicity. The interaction between the xenobiotic and the bio...

ESTIMATION OF CHEMICAL SPECIFIC PARAMETERS WITHIN PHYSIOLOGICALLY BASED PHARMACOKINETIC/PHARMACODYNAMIC MODELS

EPA Science Inventory

While relationships between chemical structure and observed properties or activities (QSAR - quantitative structure activity relationship) can be used to predict the behavior of unknown chemicals, this method is semiempirical in nature relying on high quality experimental data to...

The Effects of Classroom Goal Structures on the Creativity of Junior High School Students

ERIC Educational Resources Information Center

Peng, Shu-Ling; Cherng, Biing-Lin; Chen, Hsueh-Chih

2013-01-01

Previous studies have indicated that situational factors can influence students' creativity. However, no studies have specifically examined the relationship between classroom goal structures and student creativity during real classroom activities. For this study, we recruited 232 seventh-grade students from Taipei City and randomly divided them…

Three-dimensional quantitative structure-activity relationship study on anti-cancer activity of 3,4-dihydroquinazoline derivatives against human lung cancer A549 cells

NASA Astrophysics Data System (ADS)

Cho, Sehyeon; Choi, Min Ji; Kim, Minju; Lee, Sunhoe; Lee, Jinsung; Lee, Seok Joon; Cho, Haelim; Lee, Kyung-Tae; Lee, Jae Yeol

2015-03-01

A series of 3,4-dihydroquinazoline derivatives with anti-cancer activities against human lung cancer A549 cells were subjected to three-dimensional quantitative structure-activity relationship (3D-QSAR) studies using the comparative molecular similarity indices analysis (CoMSIA) approaches. The most potent compound, 1 was used to align the molecules. As a result, the best prediction was obtained with CoMSIA combined the steric, electrostatic, hydrophobic, hydrogen bond donor, and hydrogen bond acceptor fields (q2 = 0.720, r2 = 0.897). This model was validated by an external test set of 6 compounds giving satisfactory predictive r2 value of 0.923 as well as the scrambling stability test. This model would guide the design of potent 3,4-dihydroquinazoline derivatives as anti-cancer agent for the treatment of human lung cancer.

Modeling of the relationship between dipeptide structure and dipeptide stability, permeability, and ACE inhibitory activity.

PubMed

Foltz, Martin; van Buren, Leo; Klaffke, Werner; Duchateau, Guus S M J E

2009-09-01

Selected di- and tripeptides exhibit angiotensin-I converting enzyme (ACE) inhibitory activity in vitro. However, the efficacy in vivo is most likely limited for most peptides due to low bioavailability. The purpose of this study was to identify descriptors of intestinal stability, permeability, and ACE inhibitory activity of dipeptides. A total of 228 dipeptides were synthesized; intestinal stability was obtained by in vitro digestion, intestinal permeability using Caco-2 cells and ACE inhibitory activity by an in vitro assay. Databases were constructed to study the relationship between structure and activity, permeability, and stability. Quantitative structure-activity relationship (QSAR) modeling was performed based on computed models using partial least squares regression based on 400 molecular descriptors. QSAR modeling of dipeptide stability revealed high correlation coefficients (R > 0.65) for models based on Z and X scales. However, amino acid (AA) clustering showed the best results in describing stability of dipeptides. The N-terminal AA residues Asp, Gly, and Pro as well as the C-terminal residues Pro, Ser, Thr, and Asp stabilize dipeptides toward luminal enzymatic peptide hydrolysis. QSAR modeling did not reveal significant correlation models for intestinal permeability. 2D-fingerprint models were identified describing ACE inhibitory activity of dipeptides. The intestinal stability of 12 peptides was predicted. Peptides were synthesized and stability was confirmed in simulated digestion experiments. Based on the results, specific dipeptides can be designed to meet both stability and activity criteria. However, postabsorptive ACE inhibitory activities of dipeptides in vivo are most likely limited due to the very low intestinal permeability of dipeptides.

Structure-activity relationship study of spider polyamine toxins as inhibitors of ionotropic glutamate receptors.

PubMed

Xiong, Xiao-Feng; Poulsen, Mette H; Hussein, Rama A; Nørager, Niels G; Strømgaard, Kristian

2014-12-01

The spider polyamine toxins Joro spider toxin-3 (JSTX-3) and Nephila polyamine toxins-1 and -8 (NPTX-1 and NPTX-8) are isolated from the venom of the orb-weaver spider Nephila clavata (Joro spider). They share a high degree of structural resemblance, their aromatic head groups being the only difference, and were recently found to be very potent open-channel blockers of ionotropic glutamate (iGlu) receptors. In this study we designed and synthesized a collection of 24 analogues of these toxins using a recently developed solid-phase synthetic methodology. Systematic variation in two regions of the toxins and subsequent evaluation of biological activity at AMPA and NMDA subtypes of iGlu receptors provided succinct information on structure-activity relationships. In particular, one set of analogues were found to display exquisite selectivity and potency for AMPA receptors relative to the natural products. Thus, this systematic SAR study has provided new pharmacological tools for studies of iGlu receptors. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Potential of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones against Leishmania (L.) infantum: biological activity and structure-activity relationships.

PubMed

Pinto, Erika G; Santos, Isabela O; Schmidt, Thomas J; Borborema, Samanta E T; Ferreira, Vitor F; Rocha, David R; Tempone, Andre G

2014-01-01

Naphtoquinones have been used as promising scaffolds for drug design studies against protozoan parasites. Considering the highly toxic and limited therapeutic arsenal, the global negligence with tropical diseases and the elevated prevalence of co-morbidities especially in developing countries, the parasitic diseases caused by various Leishmania species (leishmaniasis) became a significant public health threat in 98 countries. The aim of this work was the evaluation of antileishmanial in vitro potential of thirty-six 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones obtained by a three component reaction of lawsone, the appropriate aldehyde and thiols adequately substituted, exploiting the in situ generation of o-quinonemethides (o-QM) via the Knoevenagel condensation. The antileishmanial activity of the naphthoquinone derivatives was evaluated against promastigotes and intracellular amastigotes of Leishmania (Leishmania) infantum and their cytotoxicity was verified in mammalian cells. Among the thirty-six compounds, twenty-seven were effective against promastigotes, with IC50 values ranging from 8 to 189 µM; fourteen compounds eliminated the intracellular amastigotes, with IC50 values ranging from 12 to 65 µM. The compounds containing the phenyl groups at R1 and R2 and with the fluorine substituent at the phenyl ring at R2, rendered the most promising activity, demonstrating a selectivity index higher than 15 against amastigotes. A QSAR (quantitative structure activity relationship) analysis yielded insights into general structural requirements for activity of most compounds in the series. Considering the in vitro antileishmanial potential of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones and their structure-activity relationships, novel lead candidates could be exploited in future drug design studies for leishmaniasis.

Synthesis and structure-activity relationship of the first nonpeptidergic inverse agonists for the human cytomegalovirus encoded chemokine receptor US28.

PubMed

Hulshof, Janneke W; Casarosa, Paola; Menge, Wiro M P B; Kuusisto, Leena M S; van der Goot, Henk; Smit, Martine J; de Esch, Iwan J P; Leurs, Rob

2005-10-06

US28 is a human cytomegalovirus (HCMV) encoded G-protein-coupled receptor that signals in a constitutively active manner. Recently, we identified 1 [5-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylpentanenitrile] as the first reported nonpeptidergic inverse agonist for a viral-encoded chemokine receptor. Interestingly, this compound is able to partially inhibit the viral entry of HIV-1. In this study we describe the synthesis of 1 and several of its analogues and unique structure-activity relationships for this first class of small-molecule ligands for the chemokine receptor US28. Moreover, the compounds have been pharmacologically characterized as inverse agonists on US28. By modification of lead structure 1, it is shown that a 4-phenylpiperidine moiety is essential for affinity and activity. Other structural features of 1 are shown to be of less importance. These compounds define the first SAR of ligands on a viral GPCR (US28) and may therefore serve as important tools to investigate the significance of US28-mediated constitutive activity during viral infection.

Prediction of Environmental Impact of High-Energy Materials with Atomistic Computer Simulations

DTIC Science & Technology

2010-11-01

from a training set of compounds. Other methods include Quantitative Struc- ture-Activity Relationship ( QSAR ) and Quantitative Structure-Property...26 28 the development of QSPR/ QSAR models, in contrast to boiling points and critical parameters derived from empirical correlations, to improve...Quadratic Configuration Interaction Singles Doubles QSAR Quantitative Structure-Activity Relationship QSPR Quantitative Structure-Property

Photoelectron spectra and biological activity of cinnamic acid derivatives revisited.

PubMed

Novak, Igor; Klasinc, Leo; McGlynn, Sean P

2018-01-15

The electronic structures of several derivatives of cinnamic acid have been studied by UV photoelectron spectroscopy (UPS) and Green's function quantum chemical calculations. The spectra reveal the presence of dimers in the gas phase for p-coumaric and ferulic acids. The electronic structure analysis has been related to the biological properties of these compounds through the analysis of some structure-activity relationships (SAR). Copyright © 2017 Elsevier B.V. All rights reserved.

QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS FOR CHEMICAL REDUCTIONS OF ORGANIC CONTAMINANTS

EPA Science Inventory

Sufficient kinetic data on abiotic reduction reactions involving organic contaminants are now available that quantitative structure-activity relationships (QSARs) for these reactions can be developed. Over 50 QSARs have been reported, most in just the last few years, and they ar...

Quantitative Structure-Cytotoxicity Relationship of Bioactive Heterocycles by the Semi-empirical Molecular Orbital Method with the Concept of Absolute Hardness

NASA Astrophysics Data System (ADS)

Ishihara, Mariko; Sakagami, Hiroshi; Kawase, Masami; Motohashi, Noboru

The relationship between the cytotoxicity of N-heterocycles (13 4-trifluoromethylimidazole, 15 phenoxazine and 12 5-trifluoromethyloxazole derivatives), O-heterocycles (11 3-formylchromone and 20 coumarin derivatives) and seven vitamin K2 derivatives against eight tumor cell lines (HSC-2, HSC-3, HSC-4, T98G, HSG, HepG2, HL-60, MT-4) and a maximum of 15 chemical descriptors was investigated using CAChe Worksystem 4.9 project reader. After determination of the conformation of these compounds and approximation to the molecular form present in vivo (biomimetic) by CONFLEX5, the most stable structure was determined by CAChe Worksystem 4.9 MOPAC (PM3). The present study demonstrates the best relationship between the cytotoxic activity and molecular shape or molecular weight of these compounds. Their biological activities can be estimated by hardness and softness, and by using η-χ activity diagrams.

The study on molecular structure and microbiological activity of alkali metal 3-hydroxyphenylycetates

NASA Astrophysics Data System (ADS)

Samsonowicz, M.; Regulska, E.; Kowczyk-Sadowy, M.; Butarewicz, A.; Lewandowski, W.

2017-10-01

The biological activity of chemical compounds depends on their molecular structure. In this paper molecular structure of 3-hydroxyphenylacetates in comparison to 3-hydroxyphenylacetic acid was studied. FT-IR, FT-Raman and NMR spectroscopy and density functional theory (DFT) calculations was used. The B3LYP/6-311++G(d,p) hybrid functional method was used to calculate optimized geometrical structures of studied compounds. The Mulliken, APT, MK, ChelpG and NBO atomic charges as well as dipole moment and energy values were calculated. Theoretical chemical shifts in NMR spectra and the wavenumbers and intensities of the bands in vibrational spectra were analyzed. Calculated parameters were compared to experimental characteristic of studied compounds. Microbiological analysis of studied compounds was performed relative to: Bacillus subtilis, Pseudomonas aeruginosa, Escherichia coli and Klebsiella oxytoca. The relationship between spectroscopic and structure parameters of studied compounds in regard to their activity was analyzed.

Structure-Activity Relationships of a Novel Pyranopyridine Series of Gram-negative Bacterial Efflux Pump Inhibitors

PubMed Central

Nguyen, Son T.; Kwasny, Steven M.; Ding, Xiaoyuan; Cardinale, Steven C.; McCarthy, Courtney T.; Kim, Hong-Suk; Nikaido, Hiroshi; Peet, Norton P.; Williams, John D.; Bowlin, Terry L.; Opperman, Timothy J.

2015-01-01

Recently we described a novel pyranopyridine inhibitor (MBX2319) of RND-type efflux pumps of the Enterobacteriaceae. MBX2319 (3,3-dimethyl-5-cyano-8-morpholino-6-(phenethylthio)-3,4-dihydro-1H-pyrano[3,4-c]pyridine) is structurally distinct from other known Gram-negative efflux pump inhibitors (EPIs), such as 1-(1-naphthylmethyl)-piperazine (NMP), phenylalanylarginine-β-naphthylamide (PAβN), D13-9001, and the pyridopyrimidine derivatives. Here, we report the synthesis and biological evaluation of 60 new analogs of MBX2319 that were designed to probe the structure activity relationships (SARs) of the pyranopyridine scaffold. The results of these studies produced a molecular activity map of the scaffold, which identifies regions that are critical to efflux inhibitory activities and those that can be modified to improve potency, metabolic stability and solubility. Several compounds, such as 22d–f, 22i and 22k, are significantly more effective than MBX2319 at potentiating the antibacterial activity of levofloxacin and piperacillin against Escherichia coli. PMID:25818767

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.

Functionalization of peptide nucleolipid bioconjugates and their structure anti-cancer activity relationship studies.

PubMed

Rana, Niki; Cultrara, Christopher; Phillips, Mariana; Sabatino, David

2017-09-01

In the search for more potent peptide-based anti-cancer conjugates the generation of new, functionally diverse nucleolipid derived D-(KLAKLAK) 2 -AK sequences has enabled a structure and anti-cancer activity relationship study. A reductive amination approach was key for the synthesis of alkylamine, diamine and polyamine derived nucleolipids as well as those incorporating heterocyclic functionality. The carboxy-derived nucleolipids were then coupled to the C-terminus of the D-(KLAKLAK) 2 -AK killer peptide sequence and produced with and without the FITC fluorophore for investigating biological activity in cancer cells. The amphiphilic, α-helical peptide-nucleolipid bioconjugates were found to exhibit variable effects on the viability of MM.1S cells, with the histamine derived nucleolipid peptide bioconjugate displaying the most significant anti-cancer effects. Thus, functionally diverse nucleolipids have been developed to fine-tune the structure and anti-cancer properties of killer peptide sequences, such as D-(KLAKLAK) 2 -AK. Copyright © 2017 Elsevier Ltd. All rights reserved.

Red Wine Tannin Structure-Activity Relationships during Fermentation and Maceration.

PubMed

Yacco, Ralph S; Watrelot, Aude A; Kennedy, James A

2016-02-03

The correlation between tannin structure and corresponding activity was investigated by measuring the thermodynamics of interaction between tannins isolated from commercial red wine fermentations and a polystyrene divinylbenzene HPLC column. Must and/or wine samples were collected throughout fermentation/maceration from five Napa Valley wineries. By varying winery, fruit source, maceration time, and cap management practice, it was considered that a reasonably large variation in commercially relevant tannin structure would result. Tannins were isolated from samples collected using low pressure chromatography and were then characterized by gel permeation chromatography and acid-catalyzed cleavage in the presence of excess phloroglucinol (phloroglucinolysis). Corresponding tannin activity was determined using HPLC by measuring the thermodynamics of interaction between isolated tannin and a polystyrene divinylbenzene HPLC column. This measurement approach was designed to determine the ability of tannins to hydrophobically interact with a hydrophobic surface. The results of this study indicate that tannin activity is primarily driven by molecular size. Compositionally, tannin activity was positively associated with seed tannins and negatively associated with skin and pigmented tannins. Although measured indirectly, the extent of tannin oxidation as determined by phloroglucinolysis conversion yield suggests that tannin oxidation at this stage of production reduces tannin activity. Based upon maceration time, this study indicates that observed increases in perceived astringency quality, if related to tannin chemistry, are driven by tannin molecular mass as opposed to pigmented tannin formation or oxidation. Overall, the results of this study give new insight into tannin structure-activity relationships which dominate during extraction.

Three-dimensional quantitative structure-activity relationship studies on c-Src inhibitors based on different docking methods.

PubMed

Bairy, Santhosh Kumar; Suneel Kumar, B V S; Bhalla, Joseph Uday Tej; Pramod, A B; Ravikumar, Muttineni

2009-04-01

c-Src kinase play an important role in cell growth and differentiation and its inhibitors can be useful for the treatment of various diseases, including cancer, osteoporosis, and metastatic bone disease. Three dimensional quantitative structure-activity relationship (3D-QSAR) studies were carried out on quinazolin derivatives inhibiting c-Src kinase. Molecular field analysis (MFA) models with four different alignment techniques, namely, GLIDE, GOLD, LIGANDFIT and Least squares based methods were developed. glide based MFA model showed better results (Leave one out cross validation correlation coefficient r(2)(cv) = 0.923 and non-cross validation correlation coefficient r(2)= 0.958) when compared with other models. These results help us to understand the nature of descriptors required for activity of these compounds and thereby provide guidelines to design novel and potent c-Src kinase inhibitors.

Design, synthesis, and structure-activity relationships of 3,4-dihydropyridopyrimidin-2(1H)-one derivatives as a novel class of sodium/calcium exchanger inhibitor.

PubMed

Hasegawa, Hirohiko; Muraoka, Masami; Ohmori, Mikiko; Matsui, Kazuki; Kojima, Atsuyuki

2005-10-01

Design, synthesis, and structure-activity relationships for 3,4-dihydropyridopyrimidin-2(1H)-one derivatives, which are aza-3,4-dihydro-2(1H)-quinazolinone derivatives, as the sodium/calcium (Na+/Ca2+) exchanger inhibitors are discussed. These studies based on 3,4-dihydro-2(1H)-quinazolinone derivatives led to the discovery of a structurally novel and potent Na+/Ca2+ exchanger inhibitor, 3,4-dihydropyridopyrimidin-2(1H)-one derivative (26), with an IC30 value of 0.02 microM. Compound 26 directly inhibited the Na+-dependent Ca2+ influx via the Na+/Ca2+ exchanger after Na+-free treatment in cardiomyocytes.

Synthesis, Structure-Activity Relationships (SAR) and in Silico Studies of Coumarin Derivatives with Antifungal Activity

PubMed Central

de Araújo, Rodrigo S. A.; Guerra, Felipe Q. S.; de O. Lima, Edeltrudes; de Simone, Carlos A.; Tavares, Josean F.; Scotti, Luciana; Scotti, Marcus T.; de Aquino, Thiago M.; de Moura, Ricardo O.; Mendonça, Francisco J. B.; Barbosa-Filho, José M.

2013-01-01

The increased incidence of opportunistic fungal infections, associated with greater resistance to the antifungal drugs currently in use has highlighted the need for new solutions. In this study twenty four coumarin derivatives were screened in vitro for antifungal activity against strains of Aspergillus. Some of the compounds exhibited significant antifungal activity with MICs values ranging between 16 and 32 μg/mL. The structure-activity relationships (SAR) study demonstrated that O-substitutions are essential for antifungal activity. It also showed that the presence of a short aliphatic chain and/or electron withdrawing groups (NO2 and/or acetate) favor activity. These findings were confirmed using density functional theory (DFT), when calculating the LUMO density. In Principal Component Analysis (PCA), two significant principal components (PCs) explained more than 60% of the total variance. The best Partial Least Squares Regression (PLS) model showed an r2 of 0.86 and q2cv of 0.64 corroborating the SAR observations as well as demonstrating a greater probe N1 interaction for active compounds. Descriptors generated by TIP correlogram demonstrated the importance of the molecular shape for antifungal activity. PMID:23306152

Synthesis and antioxidant activity of curcumin analogs.

PubMed

Zheng, Qu-Tong; Yang, Ze-Hua; Yu, Liu-Ying; Ren, Yu-Yan; Huang, Qiu-Xia; Liu, Qiu; Ma, Xiang-Yu; Chen, Zi-Kang; Wang, Zong-Bao; Zheng, Xing

2017-05-01

Numerous biological activities including antioxidant, antitumor, anti-inflammation, and antivirus of the natural product curcumin were reported. However, the clinical application of it was significantly limited by its instability, poor solubility, less body absorbing, and low bioavailability. This review focuses on the structure modification and antioxidant activity evaluation of curcumin. To study the structure-activity relationship (SAR), five series of curcumin analogs were synthesized and their antioxidant activity were evaluated in vitro. The results showed that electron-donating groups, especially the phenolic hydroxyl group are an essential component to improve the antioxidant activity.

Design, synthesis, and evaluation of cyclic amide/imide-bearing hydroxamic acid derivatives as class-selective histone deacetylase (HDAC) inhibitors.

PubMed

Shinji, Chihiro; Maeda, Satoko; Imai, Keisuke; Yoshida, Minoru; Hashimoto, Yuichi; Miyachi, Hiroyuki

2006-11-15

A series of hydroxamic acid derivatives bearing a cyclic amide/imide group as a linker and/or cap structure, prepared during our structural development studies based on thalidomide, showed class-selective potent histone deacetylase (HDAC)-inhibitory activity. Structure-activity relationship studies indicated that the steric character of the substituent introduced at the cyclic amide/imide nitrogen atom, the presence of the amide/imide carbonyl group, the hydroxamic acid structure, the shape of the linking group, and the distance between the zinc-binding hydroxamic acid group and the cap structure are all important for HDAC-inhibitory activity and class selectivity. A representative compound (30w) showed potent p21 promoter activity, comparable with that of trichostatin A (TSA), and its cytostatic activity against cells of the human prostate cell line LNCaP was more potent than that of the well-known HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA).

The Promise and Perils of Population Research on Same-Sex Families.

PubMed

Reczek, Corinne; Spiker, Russell; Liu, Hui; Crosnoe, Robert

2017-12-01

As a follow-up to our 2016 study, this article presents new findings examining the relationship between same-sex family structure and child health using the 2008-2015 National Health Interview Survey (NHIS). After discussing NIHS data problems, we examine the relationship between family structure and a broad range of child well-being outcomes, including school days lost, behavior, parent-rated health, emotional difficulties, and activity limitations. We find both similarities (school days lost, behavior, parent-rated health) and differences (emotional difficulties and activity limitations) across our two studies using different survey years, but our overall conclusions are robust. We further discuss the implications of our findings for future research on this topic, including how to account for biological relatedness in a study on child health in same-sex families.

Scalable total synthesis and comprehensive structure-activity relationship studies of the phytotoxin coronatine.

PubMed

Littleson, Mairi M; Baker, Christopher M; Dalençon, Anne J; Frye, Elizabeth C; Jamieson, Craig; Kennedy, Alan R; Ling, Kenneth B; McLachlan, Matthew M; Montgomery, Mark G; Russell, Claire J; Watson, Allan J B

2018-03-16

Natural phytotoxins are valuable starting points for agrochemical design. Acting as a jasmonate agonist, coronatine represents an attractive herbicidal lead with novel mode of action, and has been an important synthetic target for agrochemical development. However, both restricted access to quantities of coronatine and a lack of a suitably scalable and flexible synthetic approach to its constituent natural product components, coronafacic and coronamic acids, has frustrated development of this target. Here, we report gram-scale production of coronafacic acid that allows a comprehensive structure-activity relationship study of this target. Biological assessment of a >120 member library combined with computational studies have revealed the key determinants of potency, rationalising hypotheses held for decades, and allowing future rational design of new herbicidal leads based on this template.

The marketing activities of hospitals: environmental, organizational, and managerial influences.

PubMed

Myrtle, R C; Martinez, C F

1991-03-01

This article reports the results of a study designed to examine the relationship of environmental, organizational and structural factors, perceptions of key decision makers about competitive conditions, and changes in operational performance with the level of the marketing activities engaged in by 145 California hospitals. Measures assessing the impact of environmental conditions and the perception of the key decision makers were found to be related to the marketing activities of the organization. However, the relationship between measures which examined the structural and performance impacts on the marketing activities did not demonstrate the same predictive ability. The results suggest that marketing activities were affected by the key decision maker's assessment of the competitive nature of the environment, influence of key stakeholders, and tangible changes in the organization's task environment. Performance and other measures were not found to be as influential in determining these activities.

Aziridinyl-substituted benzo-1,4-quinones: A preliminary investigation on the theoretical and experimental studies of their structure and spectroscopic properties

NASA Astrophysics Data System (ADS)

Šarlauskas, Jonas; Tamulienė, Jelena; Čėnas, Narimantas

2017-05-01

The detailed structure, chemical and spectroscopic properties of the derivatives of the selected 2,5-bis(1-aziridinyl)-benzo-1,4-quinone conformers were studied by applying quantum chemical and experimental methods. The relationship between the structure and chemical activity of the selected 3 bifunctional bioreductive quinonic anticancer agents - aziridinyl benzoquinones (AzBQ compounds) was obtained. The results obtained showed that the position of aziridine rings influenced by the chemical activity of the investigated compound were more significant than the substitutions of the benzene ring of the AzBQ compounds. The solvents influencing this activity were obtained, too.

Quantitative structure-activity relationship (QSAR) for insecticides: development of predictive in vivo insecticide activity models.

PubMed

Naik, P K; Singh, T; Singh, H

2009-07-01

Quantitative structure-activity relationship (QSAR) analyses were performed independently on data sets belonging to two groups of insecticides, namely the organophosphates and carbamates. Several types of descriptors including topological, spatial, thermodynamic, information content, lead likeness and E-state indices were used to derive quantitative relationships between insecticide activities and structural properties of chemicals. A systematic search approach based on missing value, zero value, simple correlation and multi-collinearity tests as well as the use of a genetic algorithm allowed the optimal selection of the descriptors used to generate the models. The QSAR models developed for both organophosphate and carbamate groups revealed good predictability with r(2) values of 0.949 and 0.838 as well as [image omitted] values of 0.890 and 0.765, respectively. In addition, a linear correlation was observed between the predicted and experimental LD(50) values for the test set data with r(2) of 0.871 and 0.788 for both the organophosphate and carbamate groups, indicating that the prediction accuracy of the QSAR models was acceptable. The models were also tested successfully from external validation criteria. QSAR models developed in this study should help further design of novel potent insecticides.

The dynamic relationship between structural change and CO2 emissions in Malaysia: a cointegrating approach.

PubMed

Ali, Wajahat; Abdullah, Azrai; Azam, Muhammad

2017-05-01

The current study investigates the dynamic relationship between structural changes, real GDP per capita, energy consumption, trade openness, population density, and carbon dioxide (CO 2 ) emissions within the EKC framework over a period 1971-2013. The study used the autoregressive distributed lagged (ARDL) approach to investigate the long-run relationship between the selected variables. The study also employed the dynamic ordinary least squared (DOLS) technique to obtain the robust long-run estimates. Moreover, the causal relationship between the variables is explored using the VECM Granger causality test. Empirical results reveal a negative relationship between structural change and CO 2 emissions in the long run. The results indicate a positive relationship between energy consumption, trade openness, and CO 2 emissions. The study applied the turning point formula of Itkonen (2012) rather than the conventional formula of the turning point. The empirical estimates of the study do not support the presence of the EKC relationship between income and CO 2 emissions. The Granger causality test indicates the presence of long-run bidirectional causality between energy consumption, structural change, and CO 2 emissions in the long run. Economic growth, openness to trade, and population density unidirectionally cause CO 2 emissions. These results suggest that the government should focus more on information-based services rather than energy-intensive manufacturing activities. The feedback relationship between energy consumption and CO 2 emissions suggests that there is an ominous need to refurbish the energy-related policy reforms to ensure the installations of some energy-efficient modern technologies.

Chromanyl-isoxazolidines as Antibacterial agents: Synthesis, Biological Evaluation, Quantitative Structure Activity Relationship, and Molecular Docking Studies.

PubMed

Singh, Gagandeep; Sharma, Anuradha; Kaur, Harpreet; Ishar, Mohan Paul S

2016-02-01

Regio- and stereoselective 1,3-dipolar cycloadditions of C-(chrom-4-one-3-yl)-N-phenylnitrones (N) with different mono-substituted, disubstituted, and cyclic dipolarophiles were carried out to obtain substituted N-phenyl-3'-(chrom-4-one-3-yl)-isoxazolidines (1-40). All the synthesized compounds were assayed for their in vitro antibacterial activity and display significant inhibitory potential; in particular, compound 32 exhibited good inhibitory activity against Salmonella typhymurium-1 & Salmonella typhymurium-2 with minimum inhibitory concentration value of 1.56 μg/mL and also showed good potential against methicillin-resistant Staphylococcus aureus with minimum inhibitory concentration 3.12 μg/mL. Quantitative structure activity relationship investigations with stepwise multiple linear regression analysis and docking simulation studies have been performed for validation of the observed antibacterial potential of the investigated compounds for determination of the most important parameters regulating antibacterial activities. © 2015 John Wiley & Sons A/S.

Structure-activity relationships of an antimicrobial peptide plantaricin s from two-peptide class IIb bacteriocins.

PubMed

Soliman, Wael; Wang, Liru; Bhattacharjee, Subir; Kaur, Kamaljit

2011-04-14

Class IIb bacteriocins are ribosomally synthesized antimicrobial peptides comprising two different peptides synergistically acting in equal amounts for optimal potency. In this study, we demonstrate for the first time potent (nanomolar) antimicrobial activity of a representative class IIb bacteriocin, plantaricin S (Pls), against four pathogenic gram-positive bacteria, including Listeria monocytogenes. The structure-activity relationships for Pls were studied using activity assays, circular dichroism (CD), and molecular dynamics (MD) simulations. The two Pls peptides and five Pls derived fragments were synthesized. The CD spectra of the Pls and selected fragments revealed helical conformations in aqueous 2,2,2-trifluoroethanol. The MD simulations showed that when the two Pls peptides are in antiparallel orientation, the helical regions interact and align, mediated by strong attraction between conserved GxxxG/AxxxA motifs. The results strongly correlate with the antimicrobial activity suggesting that helix-helix alignment of the two Pls peptides and interaction between the conserved motifs are crucial for interaction with the target cell membrane.

Ensemble averaged structure–function relationship for nanocrystals: effective superparamagnetic Fe clusters with catalytically active Pt skin [Ensemble averaged structure-function relationship for composite nanocrystals: magnetic bcc Fe clusters with catalytically active fcc Pt skin

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

Petkov, Valeri; Prasai, Binay; Shastri, Sarvjit

Practical applications require the production and usage of metallic nanocrystals (NCs) in large ensembles. Besides, due to their cluster-bulk solid duality, metallic NCs exhibit a large degree of structural diversity. This poses the question as to what atomic-scale basis is to be used when the structure–function relationship for metallic NCs is to be quantified precisely. In this paper, we address the question by studying bi-functional Fe core-Pt skin type NCs optimized for practical applications. In particular, the cluster-like Fe core and skin-like Pt surface of the NCs exhibit superparamagnetic properties and a superb catalytic activity for the oxygen reduction reaction,more » respectively. We determine the atomic-scale structure of the NCs by non-traditional resonant high-energy X-ray diffraction coupled to atomic pair distribution function analysis. Using the experimental structure data we explain the observed magnetic and catalytic behavior of the NCs in a quantitative manner. Lastly, we demonstrate that NC ensemble-averaged 3D positions of atoms obtained by advanced X-ray scattering techniques are a very proper basis for not only establishing but also quantifying the structure–function relationship for the increasingly complex metallic NCs explored for practical applications.« less

Lysine acetyltransferase inhibitors: structure-activity relationships and potential therapeutic implications.

PubMed

Fiorentino, Francesco; Mai, Antonello; Rotili, Dante

2018-05-01

Lysine acetylation is a post-translational modification of both histone and nonhistone proteins that is catalyzed by lysine acetyltransferases and plays a key role in numerous biological contexts. The dysregulation of this enzyme activity is implicated in many human pathologies such as cancer, neurological and inflammatory disorders. Many lysine acetyltransferase inhibitors (KATi) have been developed so far, but there is still the need for new, more potent, metabolically stable and selective KATi as chemical tools for studying KAT biology and/or as potential therapeutic agents. This review will examine the features of KAT enzymes and related diseases, with particular emphasis on KATi (bisubstrate analogs, natural compounds and synthetic derivatives), analyzing their mechanism of action, structure-activity relationships, pharmacokinetic/pharmacodynamic properties and potential future applications.

The quantitative structure-insecticidal activity relationships from plant derived compounds against chikungunya and zika Aedes aegypti (Diptera:Culicidae) vector.

PubMed

Saavedra, Laura M; Romanelli, Gustavo P; Rozo, Ciro E; Duchowicz, Pablo R

2018-01-01

The insecticidal activity of a series of 62 plant derived molecules against the chikungunya, dengue and zika vector, the Aedes aegypti (Diptera:Culicidae) mosquito, is subjected to a Quantitative Structure-Activity Relationships (QSAR) analysis. The Replacement Method (RM) variable subset selection technique based on Multivariable Linear Regression (MLR) proves to be successful for exploring 4885 molecular descriptors calculated with Dragon 6. The predictive capability of the obtained models is confirmed through an external test set of compounds, Leave-One-Out (LOO) cross-validation and Y-Randomization. The present study constitutes a first necessary computational step for designing less toxic insecticides. Copyright © 2017 Elsevier B.V. All rights reserved.

Cytotoxic activity of aminoderivatized cationic chitosan derivatives.

PubMed

Lee, Jung-Kul; Lim, Hyun-Soo; Kim, Jung-Hoe

2002-10-21

Chitosan derivatives were prepared by dialkylaminoalkylation and reductive amination followed by quaternization. In this study, the cytotoxic activity of the chitosan derivatives was investigated and a relationship between structure and activity is suggested. The cationic chitosan derivatives elicited dose-dependent inhibitory effects on the proliferation of tumor cell lines.

Design, synthesis, and structure-activity relationship study of halogen containing 2-benzylidene-1-indanone derivatives for inhibition of LPS-stimulated ROS production in RAW 264.7 macrophages.

PubMed

Shrestha, Aarajana; Jin Oh, Hye; Kim, Mi Jin; Pun, Nirmala Tilija; Magar, Til Bahadur Thapa; Bist, Ganesh; Choi, Hongseok; Park, Pil-Hoon; Lee, Eung-Seok

2017-06-16

As a continuous effort to discover new potential anti-inflammatory agents, we systematically designed and synthesized sixty-one 2-benzylidene-1-indanone derivatives with structural modification of chalcone, and evaluated their inhibitory activity on LPS-stimulated ROS production in RAW 264.7 macrophages. Systematic structure-activity relationship study revealed that hydroxyl group in C-5, C-6, or C-7 position of indanone moiety, and ortho-, meta-, or para-fluorine, trifluoromethyl, trifluoromethoxy, and bromine functionalities in phenyl ring are important for inhibition of ROS production in LPS-stimulated RAW 264.7 macrophages. Among all the tested compounds, 6-hydroxy-2-(2-(trifluoromethoxy) benzylidene)-2,3-dihydro-1H-inden-1-one (compound 44) showed the strongest inhibitory activity of ROS production. Further studies on the mode of action revealed that compound 44 potently suppressed LPS-stimulated ROS production via modulation of NADPH oxidase. The findings of this work could be useful to design 2-benzylidene-indanone based lead compounds as novel anti-inflammatory agents. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

A Short Review of the Generation of Molecular Descriptors and Their Applications in Quantitative Structure Property/Activity Relationships.

PubMed

Sahoo, Sagarika; Adhikari, Chandana; Kuanar, Minati; Mishra, Bijay K

2016-01-01

Synthesis of organic compounds with specific biological activity or physicochemical characteristics needs a thorough analysis of the enumerable data set obtained from literature. Quantitative structure property/activity relationships have made it simple by predicting the structure of the compound with any optimized activity. For that there is a paramount data set of molecular descriptors (MD). This review is a survey on the generation of the molecular descriptors and its probable applications in QSP/AR. Literatures have been collected from a wide class of research journals, citable web reports, seminar proceedings and books. The MDs were classified according to their generation. The applications of the MDs on the QSP/AR have also been reported in this review. The MDs can be classified into experimental and theoretical types, having a sub classification of the later into structural and quantum chemical descriptors. The structural parameters are derived from molecular graphs or topology of the molecules. Even the pixel of the molecular image can be used as molecular descriptor. In QSPR studies the physicochemical properties include boiling point, heat capacity, density, refractive index, molar volume, surface tension, heat of formation, octanol-water partition coefficient, solubility, chromatographic retention indices etc. Among biological activities toxicity, antimalarial activity, sensory irritant, potencies of local anesthetic, tadpole narcosis, antifungal activity, enzyme inhibiting activity are some important parameters in the QSAR studies. The classification of the MDs is mostly generic in nature. The application of the MDs in QSP/AR also has a generic link. Experimental MDs are more suitable in correlation analysis than the theoretical ones but are more expensive for generation. In advent of sophisticated computational tools and experimental design proliferation of MDs is inevitable, but for a highly optimized MD, studies on generation of MD is an unending process.

Structure-Activity Relationship and Molecular Mechanics Reveal the Importance of Ring Entropy in the Biosynthesis and Activity of a Natural Product.

PubMed

Tran, Hai L; Lexa, Katrina W; Julien, Olivier; Young, Travis S; Walsh, Christopher T; Jacobson, Matthew P; Wells, James A

2017-02-22

Macrocycles are appealing drug candidates due to their high affinity, specificity, and favorable pharmacological properties. In this study, we explored the effects of chemical modifications to a natural product macrocycle upon its activity, 3D geometry, and conformational entropy. We chose thiocillin as a model system, a thiopeptide in the ribosomally encoded family of natural products that exhibits potent antimicrobial effects against Gram-positive bacteria. Since thiocillin is derived from a genetically encoded peptide scaffold, site-directed mutagenesis allows for rapid generation of analogues. To understand thiocillin's structure-activity relationship, we generated a site-saturation mutagenesis library covering each position along thiocillin's macrocyclic ring. We report the identification of eight unique compounds more potent than wild-type thiocillin, the best having an 8-fold improvement in potency. Computational modeling of thiocillin's macrocyclic structure revealed a striking requirement for a low-entropy macrocycle for activity. The populated ensembles of the active mutants showed a rigid structure with few adoptable conformations while inactive mutants showed a more flexible macrocycle which is unfavorable for binding. This finding highlights the importance of macrocyclization in combination with rigidifying post-translational modifications to achieve high-potency binding.

Anti-proliferation activity of terpenoids isolated from Euphorbia kansui in human cancer cells and their structure-activity relationship.

PubMed

Hou, Jin-Jun; Shen, Yao; Yang, Zhou; Fang, Lin; Cai, Lu-Ying; Yao, Shuai; Long, Hua-Li; Wu, Wan-Ying; Guo, De-An

2017-10-01

Euphorbia kansui is a commonly used traditional Chinese medicine for the treatment of edema, pleural effusion, and asthma, etc. According to the previous researches, terpenoids in E. kansui possess various biological activities, e.g., anti-virus, anti-allergy, antitumor effects. In this work, twenty five terpenoids were isolated from E. kansui, including thirteen ingenane- and eight jatrophane-type diterpenoids (with two new compounds, kansuinin P and Q) and four triterpenoids. Eighteen of them were analyzed by MTS assay for in vitro anticancer activity in five human cancer cell lines. Structure-activity relationship for 12 ingenane-type diterpenoids in colorectal cancer Colo205 cells were preliminary studied. Significant anti-proliferation activities were observed in human melanoma cells breast cancer MDA-MB-435 cells and Colo205 cells. More than half of the isolated ingenane-type diterpenoids showed inhibitory activities in MDA-MB-435 cells. Eight ingenane- and one jatrophane-type diterpenoids possessed much lower IC 50 values in MDA-MB-435 cells than positive control staurosporine. Preliminary structure-activity relationship analysis showed that substituent on position 20 was important for the activity of ingenane-type diterpenoids in Colo205 cells and substituent on position 3 contributed more significant biological activity of the compounds than that on position 5 in both MDA-MB-435 and Colo205 cells. Copyright © 2017 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

Synthesis, crystal structure, ABTS radical-scavenging activity, antimicrobial and docking studies of some novel quinoline derivatives

NASA Astrophysics Data System (ADS)

Tabassum, Sumaiya; Suresha Kumara, T. H.; Jasinski, Jerry P.; Millikan, Sean P.; Yathirajan, H. S.; Sujan Ganapathy, P. S.; Sowmya, H. B. V.; More, Sunil S.; Nagendrappa, Gopalpur; Kaur, Manpreet; Jose, Gilish

2014-07-01

In this study, a series of nine novel 2-chloroquinolin-3-yl ester derivatives have been synthesized via a two-step protocol from 2-chloroquinoline-3-carbaldehyde. The structures of all these compounds were confirmed by spectral data. The single crystal X-ray structure of two derivatives, (2-chloroquinolin-3-yl)methyl acetate [6a] and (2-chloro-6-methylquinolin-3-yl)methyl acetate [6e] have also been determined. The synthesized compounds were further evaluated for their ABTS radical-scavenging activity and antimicrobial activities. Amongst all the tested compounds, 6a exhibited maximum scavenging activity with ABTS. Concerning antibacterial and antifungal activities, compound (2-chloro-6-methoxyquinolin-3-yl)methyl 2,4-dichlorobenzoate [6i] was found to be the most active in the series against B. subtilis, S. aureus, E. coli, K. pneumonia, C. albicans and A. niger species. The structure-antimicrobial activity relationship of these derivatives were studied using Autodock.

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.

Relationships for electron-vibrational coupling in conjugated π organic systems

NASA Astrophysics Data System (ADS)

O'Neill, L.; Lynch, P.; McNamara, M.; Byrne, H. J.

2005-06-01

A series of π conjugated systems were studied by absorption, photoluminescence and vibrational spectroscopy. As is common for these systems, a linear relationship between the positioning of the absorption and photoluminescence maxima plotted against inverse conjugation length is observed. The relationships are in good agreement with the simple particle in a box method, one of the earliest descriptions of the properties of one-dimensional organic molecules. In addition to the electronic transition energies, it was observed that the Stokes shift also exhibited a well-defined relationship with increasing conjugation length, implying a correlation between the electron-vibrational coupling and chain length. This correlation is further examined using Raman spectroscopy, whereby the integrated Raman scattering is seen to behave superlinearly with chain length. There is a clear indication that the vibrational activity and thus nonradiative decay processes are controllable through molecular structure. The correlations between the Stokes energies and the vibrational structure are also observed in a selection of PPV based polymers and a clear trend of increasing luminescence efficiency with decreasing vibrational activity and Stokes shift is observable. The implications of such structure property relationships in terms of materials design are discussed.

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.

A Comparative Study on Selective PPAR Modulators through Quantitative Structure-activity Relationship, Pharmacophore and Docking Analyses.

PubMed

Nandy, Ashis; Roy, Kunal; Saha, Achintya

2018-01-01

Metabolic syndrome is a matrix of different metabolic disorders which are the leading cause of death in human beings. Peroxysome proliferated activated receptor (PPAR) is a nuclear receptor involved in metabolism of fats and glucose. In order to explore structural requirements for selective PPAR modulators to control lipid and carbohydrate metabolism, the multi-cheminformatics studies have been performed. In silico modeling studies have been performed on a diverse set of PPAR modulators through quantitative structure-activity relationship (QSAR), pharmacophore mapping and docking studies. It is observed that the presence of an amide fragment (-CONHRPh) has a detrimental effect while an aliphatic ether linkage has a beneficial effect on PPARα modulation. On the other hand, the presence of an amide fragment has a positive effect on PPARδ modulation, but the aliphatic ether linkage and substituted aromatic ring in the molecular scaffold are very much essential for imparting potent and selective PPARγ modulation. Negative ionizable features (i.e. polar fragments) must be present in PPARδ and α modulators, but a hydrophobic feature is the prime requirement for PPARγ modulation. Here, the essential structural features have been explored for selective modulation of each subtype of PPAR in order to design new modulators with improved activity/selectivity. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Analysis of structural relationship among the occupational dysfunction on the psychological problem in healthcare workers: a study using structural equation modeling

PubMed Central

Kyougoku, Makoto

2015-01-01

Purpose. The purpose of this study is to demonstrate the hypothetical model based on structural relationship with the occupational dysfunction on psychological problems (stress response, burnout syndrome, and depression) in healthcare workers. Method. Three cross sectional studies were conducted to assess the following relations: (1) occupational dysfunction on stress response (n = 468), (2) occupational dysfunction on burnout syndrome (n = 1,142), and (3) occupational dysfunction on depression (n = 687). Personal characteristics were collected through a questionnaire (such as age, gender, and job category, opportunities for refreshment, time spent on leisure activities, and work relationships) as well as the Classification and Assessment of Occupational Dysfunction (CAOD). Furthermore, study 1 included the Stress Response Scale-18 (SRS-18), study 2 used the Japanese Burnout Scale (JBS), and study 3 employed the Center for Epidemiological Studies Depression Scale (CES-D). The Kolmogorov–Smirnov test, confirmatory factor analysis (CFA), exploratory factor analysis (EFA), and path analysis of structural equation modeling (SEM) analysis were used in all of the studies. EFA and CFA were used to measure structural validity of four assessments; CAOD, SRS-18, JBS, and CES-D. For examination of a potential covariate, we assessed the correlation of the total and factor score of CAOD and personal factors in all studies. Moreover, direct and indirect effects of occupational dysfunction on stress response (Study 1), burnout syndrome (Study 2), and depression (Study 3) were also analyzed. Results. In study 1, CAOD had 16 items and 4 factors. In Study 2 and 3, CAOD had 16 items and 5 factors. SRS-18 had 18 items and 3 factors, JBS had 17 items and 3 factors, and CES-D had 20 items and 4 factors. All studies found that there were significant correlations between the CAOD total score and the personal factor that included opportunities for refreshment, time spent on leisure activities, and work relationships (p < 0.01). The hypothesis model results suggest that the classification of occupational dysfunction had good fit on the stress response (RMSEA = 0.061, CFI = 0.947, and TLI = 0.943), burnout syndrome (RMSEA = 0.076, CFI = 0.919, and TLI = 0.913), and depression (RMSEA = 0.060, CFI = 0.922, TLI = 0.917). Moreover, the detected covariates include opportunities for refreshment, time spent on leisure activities, and work relationships on occupational dysfunction. Conclusion. Our findings indicate that psychological problems are associated with occupational dysfunction in healthcare workers. Reduction of occupational dysfunction might be a strategy of better preventive occupational therapies for healthcare workers with psychological problems. However, longitudinal studies will be needed to determine a causal relationship. PMID:26618078

Analysis of structural relationship among the occupational dysfunction on the psychological problem in healthcare workers: a study using structural equation modeling.

PubMed

Teraoka, Mutsumi; Kyougoku, Makoto

2015-01-01

Purpose. The purpose of this study is to demonstrate the hypothetical model based on structural relationship with the occupational dysfunction on psychological problems (stress response, burnout syndrome, and depression) in healthcare workers. Method. Three cross sectional studies were conducted to assess the following relations: (1) occupational dysfunction on stress response (n = 468), (2) occupational dysfunction on burnout syndrome (n = 1,142), and (3) occupational dysfunction on depression (n = 687). Personal characteristics were collected through a questionnaire (such as age, gender, and job category, opportunities for refreshment, time spent on leisure activities, and work relationships) as well as the Classification and Assessment of Occupational Dysfunction (CAOD). Furthermore, study 1 included the Stress Response Scale-18 (SRS-18), study 2 used the Japanese Burnout Scale (JBS), and study 3 employed the Center for Epidemiological Studies Depression Scale (CES-D). The Kolmogorov-Smirnov test, confirmatory factor analysis (CFA), exploratory factor analysis (EFA), and path analysis of structural equation modeling (SEM) analysis were used in all of the studies. EFA and CFA were used to measure structural validity of four assessments; CAOD, SRS-18, JBS, and CES-D. For examination of a potential covariate, we assessed the correlation of the total and factor score of CAOD and personal factors in all studies. Moreover, direct and indirect effects of occupational dysfunction on stress response (Study 1), burnout syndrome (Study 2), and depression (Study 3) were also analyzed. Results. In study 1, CAOD had 16 items and 4 factors. In Study 2 and 3, CAOD had 16 items and 5 factors. SRS-18 had 18 items and 3 factors, JBS had 17 items and 3 factors, and CES-D had 20 items and 4 factors. All studies found that there were significant correlations between the CAOD total score and the personal factor that included opportunities for refreshment, time spent on leisure activities, and work relationships (p < 0.01). The hypothesis model results suggest that the classification of occupational dysfunction had good fit on the stress response (RMSEA = 0.061, CFI = 0.947, and TLI = 0.943), burnout syndrome (RMSEA = 0.076, CFI = 0.919, and TLI = 0.913), and depression (RMSEA = 0.060, CFI = 0.922, TLI = 0.917). Moreover, the detected covariates include opportunities for refreshment, time spent on leisure activities, and work relationships on occupational dysfunction. Conclusion. Our findings indicate that psychological problems are associated with occupational dysfunction in healthcare workers. Reduction of occupational dysfunction might be a strategy of better preventive occupational therapies for healthcare workers with psychological problems. However, longitudinal studies will be needed to determine a causal relationship.

Effect of substituents on prediction of TLC retention of tetra-dentate Schiff bases and their Copper(II) and Nickel(II) complexes.

PubMed

Stevanović, Nikola R; Perušković, Danica S; Gašić, Uroš M; Antunović, Vesna R; Lolić, Aleksandar Đ; Baošić, Rada M

2017-03-01

The objectives of this study were to gain insights into structure-retention relationships and to propose the model to estimating their retention. Chromatographic investigation of series of 36 Schiff bases and their copper(II) and nickel(II) complexes was performed under both normal- and reverse-phase conditions. Chemical structures of the compounds were characterized by molecular descriptors which are calculated from the structure and related to the chromatographic retention parameters by multiple linear regression analysis. Effects of chelation on retention parameters of investigated compounds, under normal- and reverse-phase chromatographic conditions, were analyzed by principal component analysis, quantitative structure-retention relationship and quantitative structure-activity relationship models were developed on the basis of theoretical molecular descriptors, calculated exclusively from molecular structure, and parameters of retention and lipophilicity. Copyright © 2016 John Wiley & Sons, Ltd.

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.

Phyto-fungicides: Structure activity relationships of the thymol derivatives against Rhizoctonia solani

USDA-ARS?s Scientific Manuscript database

Thymol, the key component of thyme oil and its derivatives were evaluated for their structure activity relationship as fungicide against Rhizoctonia solani. Since plant based chemicals are considered as “Generally Recognized as Safe” (GRAS) chemicals, there is a great potential to use phytochemicals...

ESTIMATION OF MICROBIAL REDUCTIVE TRANSFORMATION RATES FOR CHLORINATED BENZENES AND PHENOLS USING A QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP APPROACH

EPA Science Inventory

A set of literature data was used to derive several quantitative structure-activity relationships (QSARs) to predict the rate constants for the microbial reductive dehalogenation of chlorinated aromatics. Dechlorination rate constants for 25 chloroaromatics were corrected for th...

A review of the global relationship among freshwater fish, autotrophic activity, and regional climate

USGS Publications Warehouse

Deines, Andrew M.; Bunnell, David B.; Rogers, Mark W.; Beard, T. Douglas; Taylor, William W.

2015-01-01

The relationship between autotrophic activity and freshwater fish populations is an important consideration for ecologists describing trophic structure in aquatic communities, fisheries managers tasked with increasing sustainable fisheries development, and fish farmers seeking to maximize production. Previous studies of the empirical relationships of autotrophic activity and freshwater fish yield have found positive relationships but were limited by small sample sizes, small geographic scopes, and the inability to compare patterns among many types of measurement techniques. Individual studies and reviews have also lacked consistent consideration of regional climate factors which may inform relationships between fisheries and autotrophic activity. We compiled data from over 700 freshwater systems worldwide and used meta-analysis and linear models to develop a comprehensive global synthesis between multiple metrics of autotrophic activity, fisheries, and climate indicators. Our results demonstrate that multiple metrics of fish (i.e., catch per unit effort, yield, and production) increase with autotrophic activity across a variety of fisheries. At the global scale additional variation in this positive relationship can be ascribed to regional climate differences (i.e., temperature and precipitation) across systems. Our results provide a method and proof-of-concept for assessing inland fisheries production at the global scale, where current estimates are highly uncertain, and may therefore inform the continued sustainable use of global inland fishery resources.

Hologram quantitative structure-activity relationship and comparative molecular field analysis studies within a series of tricyclic phthalimide HIV-1 integrase inhibitors.

PubMed

Magalhães, Uiaran de Oliveira; Souza, Alessandra Mendonça Teles de; Albuquerque, Magaly Girão; Brito, Monique Araújo de; Bello, Murilo Lamim; Cabral, Lucio Mendes; Rodrigues, Carlos Rangel

2013-01-01

Acquired immunodeficiency syndrome is a public health problem worldwide caused by the Human immunodeficiency virus (HIV). Treatment with antiretroviral drugs is the best option for viral suppression, reducing morbidity and mortality. However, viral resistance in HIV-1 therapy has been reported. HIV-1 integrase (IN) is an essential enzyme for effective viral replication and an attractive target for the development of new inhibitors. In the study reported here, two- and three-dimensional quantitative structure-activity relationship (2D/3D-QSAR) studies, applying hologram quantitative structure-activity relationship (HQSAR) and comparative molecular field analysis (CoMFA) methods, respectively, were performed on a series of tricyclic phthalimide HIV-1 IN inhibitors. The best HQSAR model (q (2) = 0.802, r (2) = 0.972) was obtained using atoms, bonds, and connectivity as the fragment distinction, a fragment size of 2-5 atoms, hologram length of 61 bins, and six components. The best CoMFA model (q (2) = 0.748, r (2) = 0.974) was obtained with alignment of all atoms of the tricyclic phthalimide moiety (alignment II). The HQSAR contribution map identified that the carbonyl-hydroxy-aromatic nitrogen motif made a positive contribution to the activity of the compounds. Furthermore, CoMFA contour maps suggested that bulky groups in meta and para positions in the phenyl ring would increase the biological activity of this class. The conclusions of this work may lead to a better understanding of HIV-1 IN inhibition and contribute to the design of new and more potent derivatives.

Antitumor potential of crown ethers: structure-activity relationships, cell cycle disturbances, and cell death studies of a series of ionophores.

PubMed

Marjanović, Marko; Kralj, Marijeta; Supek, Fran; Frkanec, Leo; Piantanida, Ivo; Smuc, Tomislav; Tusek-Bozić, Ljerka

2007-03-08

The present paper demonstrates the antiproliferative ability and structure-activity relationships (SAR) of 14 crown and aza-crown ether analogues on five tumor-cell types. The most active compounds were di-tert-butyldicyclohexano-18-crown-6 (3), which exhibited cytotoxicity in the submicromolar range, and di-tert-butyldibenzo-18-crown-6 (5) (IC50 values of approximately 2 microM). Also, 3 and 5 induced marked influence on the cell cycle phase distribution--strong G1 arrest, followed by the induction of apoptosis. A computational SAR modeling effort offers insight into possible mechanisms of crown ether biological activity, presumably involving penetration into cell membranes, and points out structural features of molecules important for this activity. The results reveal that crown ethers possess marked tumor-cell growth inhibitory activity, the extent of which depends on the characteristics of the hydrophilic macrocylic cavity and the surrounding hydrophobic ring. Our work supports the hypothesis that crown ether compounds inhibit tumor-cell growth by disrupting potassium ion homeostasis, which in turn leads to cell cycle perturbations and apoptosis.

Oximes: Inhibitors of Human Recombinant Acetylcholinesterase. A Structure-Activity Relationship (SAR) Study

PubMed Central

Sepsova, Vendula; Karasova, Jana Zdarova; Korabecny, Jan; Dolezal, Rafael; Zemek, Filip; Bennion, Brian J.; Kuca, Kamil

2013-01-01

Acetylcholinesterase (AChE) reactivators were developed for the treatment of organophosphate intoxication. Standard care involves the use of anticonvulsants (e.g., diazepam), parasympatolytics (e.g., atropine) and oximes that restore AChE activity. However, oximes also bind to the active site of AChE, simultaneously acting as reversible inhibitors. The goal of the present study is to determine how oxime structure influences the inhibition of human recombinant AChE (hrAChE). Therefore, 24 structurally different oximes were tested and the results compared to the previous eel AChE (EeAChE) experiments. Structural factors that were tested included the number of pyridinium rings, the length and structural features of the linker, and the number and position of the oxime group on the pyridinium ring. PMID:23959117

TIPdb-3D: the three-dimensional structure database of phytochemicals from Taiwan indigenous plants.

PubMed

Tung, Chun-Wei; Lin, Ying-Chi; Chang, Hsun-Shuo; Wang, Chia-Chi; Chen, Ih-Sheng; Jheng, Jhao-Liang; Li, Jih-Heng

2014-01-01

The rich indigenous and endemic plants in Taiwan serve as a resourceful bank for biologically active phytochemicals. Based on our TIPdb database curating bioactive phytochemicals from Taiwan indigenous plants, this study presents a three-dimensional (3D) chemical structure database named TIPdb-3D to support the discovery of novel pharmacologically active compounds. The Merck Molecular Force Field (MMFF94) was used to generate 3D structures of phytochemicals in TIPdb. The 3D structures could facilitate the analysis of 3D quantitative structure-activity relationship, the exploration of chemical space and the identification of potential pharmacologically active compounds using protein-ligand docking. Database URL: http://cwtung.kmu.edu.tw/tipdb. © The Author(s) 2014. Published by Oxford University Press.

TIPdb-3D: the three-dimensional structure database of phytochemicals from Taiwan indigenous plants

PubMed Central

Tung, Chun-Wei; Lin, Ying-Chi; Chang, Hsun-Shuo; Wang, Chia-Chi; Chen, Ih-Sheng; Jheng, Jhao-Liang; Li, Jih-Heng

2014-01-01

The rich indigenous and endemic plants in Taiwan serve as a resourceful bank for biologically active phytochemicals. Based on our TIPdb database curating bioactive phytochemicals from Taiwan indigenous plants, this study presents a three-dimensional (3D) chemical structure database named TIPdb-3D to support the discovery of novel pharmacologically active compounds. The Merck Molecular Force Field (MMFF94) was used to generate 3D structures of phytochemicals in TIPdb. The 3D structures could facilitate the analysis of 3D quantitative structure–activity relationship, the exploration of chemical space and the identification of potential pharmacologically active compounds using protein–ligand docking. Database URL: http://cwtung.kmu.edu.tw/tipdb. PMID:24930145

Peers' Perceived Support, Student Engagement in Academic Activities and Life Satisfaction: A Structural Equation Modeling Approach

ERIC Educational Resources Information Center

Hakimzadeh, Rezvan; Besharat, Mohammad-Ali; Khaleghinezhad, Seyed Ali; Ghorban Jahromi, Reza

2016-01-01

This study investigates the relationships among peers' perceived support, life satisfaction, and student engagement in academic activities. Three hundred and fifteen Iranian students (172 boys and 143 girls) who were studying in one suburb of Tehran participated in this study. All participants were asked to complete Peers' Perceived Support scale…

In Vitro Antioxidant Activity of Selected 4-Hydroxy-chromene-2-one Derivatives—SAR, QSAR and DFT Studies

PubMed Central

Mladenović, Milan; Mihailović, Mirjana; Bogojević, Desanka; Matić, Sanja; Nićiforović, Neda; Mihailović, Vladimir; Vuković, Nenad; Sukdolak, Slobodan; Solujić, Slavica

2011-01-01

The series of fifteen synthesized 4-hydroxycoumarin derivatives was subjected to antioxidant activity evaluation in vitro, through total antioxidant capacity, 1,1-diphenyl-2-picryl-hydrazyl (DPPH), hydroxyl radical, lipid peroxide scavenging and chelating activity. The highest activity was detected during the radicals scavenging, with 2b, 6b, 2c, and 4c noticed as the most active. The antioxidant activity was further quantified by the quantitative structure-activity relationships (QSAR) studies. For this purpose, the structures were optimized using Paramethric Method 6 (PM6) semi-empirical and Density Functional Theory (DFT) B3LYP methods. Bond dissociation enthalpies of coumarin 4-OH, Natural Bond Orbital (NBO) gained hybridization of the oxygen, acidity of the hydrogen atom and various molecular descriptors obtained, were correlated with biological activity, after which we designed 20 new antioxidant structures, using the most favorable structural motifs, with much improved predicted activity in vitro. PMID:21686153

Applications of genetic algorithms on the structure-activity relationship analysis of some cinnamamides.

PubMed

Hou, T J; Wang, J M; Liao, N; Xu, X J

1999-01-01

Quantitative structure-activity relationships (QSARs) for 35 cinnamamides were studied. By using a genetic algorithm (GA), a group of multiple regression models with high fitness scores was generated. From the statistical analyses of the descriptors used in the evolution procedure, the principal features affecting the anticonvulsant activity were found. The significant descriptors include the partition coefficient, the molar refraction, the Hammet sigma constant of the substituents on the benzene ring, and the formation energy of the molecules. It could be found that the steric complementarity and the hydrophobic interaction between the inhibitors and the receptor were very important to the biological activity, while the contribution of the electronic effect was not so obvious. Moreover, by construction of the spline models for these four principal descriptors, the effective range for each descriptor was identified.

Methods to enable the design of bioactive small molecules targeting RNA

PubMed Central

Disney, Matthew D.; Yildirim, Ilyas; Childs-Disney, Jessica L.

2014-01-01

RNA is an immensely important target for small molecule therapeutics or chemical probes of function. However, methods that identify, annotate, and optimize RNA-small molecule interactions that could enable the design of compounds that modulate RNA function are in their infancies. This review describes recent approaches that have been developed to understand and optimize RNA motif-small molecule interactions, including Structure-Activity Relationships Through Sequencing (StARTS), quantitative structure-activity relationships (QSAR), chemical similarity searching, structure-based design and docking, and molecular dynamics (MD) simulations. Case studies described include the design of small molecules targeting RNA expansions, the bacterial A-site, viral RNAs, and telomerase RNA. These approaches can be combined to afford a synergistic method to exploit the myriad of RNA targets in the transcriptome. PMID:24357181

Methods to enable the design of bioactive small molecules targeting RNA.

PubMed

Disney, Matthew D; Yildirim, Ilyas; Childs-Disney, Jessica L

2014-02-21

RNA is an immensely important target for small molecule therapeutics or chemical probes of function. However, methods that identify, annotate, and optimize RNA-small molecule interactions that could enable the design of compounds that modulate RNA function are in their infancies. This review describes recent approaches that have been developed to understand and optimize RNA motif-small molecule interactions, including structure-activity relationships through sequencing (StARTS), quantitative structure-activity relationships (QSAR), chemical similarity searching, structure-based design and docking, and molecular dynamics (MD) simulations. Case studies described include the design of small molecules targeting RNA expansions, the bacterial A-site, viral RNAs, and telomerase RNA. These approaches can be combined to afford a synergistic method to exploit the myriad of RNA targets in the transcriptome.

2D- and 3D-quantitative structure-activity relationship studies for a series of phenazine N,N'-dioxide as antitumour agents.

PubMed

Cunha, Jonathan Da; Lavaggi, María Laura; Abasolo, María Inés; Cerecetto, Hugo; González, Mercedes

2011-12-01

Hypoxic regions of tumours are associated with increased resistance to radiation and chemotherapy. Nevertheless, hypoxia has been used as a tool for specific activation of some antitumour prodrugs, named bioreductive agents. Phenazine dioxides are an example of such bioreductive prodrugs. Our 2D-quantitative structure activity relationship studies established that phenazine dioxides electronic and lipophilic descriptors are related to survival fraction in oxia or in hypoxia. Additionally, statistically significant models, derived by partial least squares, were obtained between survival fraction in oxia and comparative molecular field analysis standard model (r² = 0.755, q² = 0.505 and F = 26.70) or comparative molecular similarity indices analysis-combined steric and electrostatic fields (r² = 0.757, q² = 0.527 and F = 14.93), and survival fraction in hypoxia and comparative molecular field analysis standard model (r² = 0.736, q² = 0.521 and F = 18.63) or comparative molecular similarity indices analysis-hydrogen bond acceptor field (r² = 0.858, q² = 0.737 and F = 27.19). Categorical classification was used for the biological parameter selective cytotoxicity emerging also good models, derived by soft independent modelling of class analogy, with both comparative molecular field analysis standard model (96% of overall classification accuracy) and comparative molecular similarity indices analysis-steric field (92% of overall classification accuracy). 2D- and 3D-quantitative structure-activity relationships models provided important insights into the chemical and structural basis involved in the molecular recognition process of these phenazines as bioreductive agents and should be useful for the design of new structurally related analogues with improved potency. © 2011 John Wiley & Sons A/S.

Using Case Studies as a Semester-Long Tool to Teach Neuroanatomy and Structure-Function Relationships to Undergraduates

PubMed Central

Kennedy, Susan

2013-01-01

In addition to being inherently interesting to students, case studies can serve as useful tools to teach neuroanatomy and demonstrate important relationships between brain structure and function. In most undergraduate courses, however, neuroanatomy is presented to students as a “unit” or chapter, much like other topics (e.g., receptors, pharmacology) covered in the course, over a period of a week or two. In this article, a relatively simple model of teaching neuroanatomy is described in which students are actively engaged in the presentation and discussion of case studies throughout the semester, following a general introduction to the structure of the nervous system. In this way, the teaching of neuroanatomy is “distributed” throughout the semester and put into a more user-friendly context for students as additional topics are introduced. Generally, students report enjoying learning brain structure using this method, and commented positively on the class activities associated with learning brain anatomy. Advantages and disadvantages of such a model are presented, as are suggestions for implementing similar models of undergraduate neuroanatomy education. PMID:24319386

Structure-function relationships in the evolutionary framework of spermine oxidase.

PubMed

Cervelli, Manuela; Salvi, Daniele; Polticelli, Fabio; Amendola, Roberto; Mariottini, Paolo

2013-06-01

Spermine oxidase is a FAD-dependent enzyme that specifically oxidizes spermine, and plays a central role in the highly regulated catabolism of polyamines in vertebrates. The spermine oxidase substrate is specifically spermine, a tetramine that plays mandatory roles in several cell functions, such as DNA synthesis, cellular proliferation, modulation of ion channels function, cellular signalling, nitric oxide synthesis and inhibition of immune responses. The oxidative products of spermine oxidase activity are spermidine, H2O2 and the aldehyde 3-aminopropanal that spontaneously turns into acrolein. In this study the reconstruction of the phylogenetic relationships among spermine oxidase proteins from different vertebrate taxa allowed to infer their molecular evolutionary history, and assisted in elucidating the conservation of structural and functional properties of this enzyme family. The amino acid residues, which have been hypothesized or demonstrated to play a pivotal role in the enzymatic activity, and substrate specificity are here analysed to obtain a comprehensive and updated view of the structure-function relationships in the evolution of spermine oxidase.

Antitumor activity of 3,4-ethylenedioxythiophene derivatives and quantitative structure-activity relationship analysis

NASA Astrophysics Data System (ADS)

Jukić, Marijana; Rastija, Vesna; Opačak-Bernardi, Teuta; Stolić, Ivana; Krstulović, Luka; Bajić, Miroslav; Glavaš-Obrovac, Ljubica

2017-04-01

The aim of this study was to evaluate nine newly synthesized amidine derivatives of 3,4- ethylenedioxythiophene (3,4-EDOT) for their cytotoxic activity against a panel of human cancer cell lines and to perform a quantitative structure-activity relationship (QSAR) analysis for the antitumor activity of a total of 27 3,4-ethylenedioxythiophene derivatives. Induction of apoptosis was investigated on the selected compounds, along with delivery options for the optimization of activity. The best obtained QSAR models include the following group of descriptors: BCUT, WHIM, 2D autocorrelations, 3D-MoRSE, GETAWAY descriptors, 2D frequency fingerprint and information indices. Obtained QSAR models should be relieved in elucidation of important physicochemical and structural requirements for this biological activity. Highly potent molecules have a symmetrical arrangement of substituents along the x axis, high frequency of distance between N and O atoms at topological distance 9, as well as between C and N atoms at topological distance 10, and more C atoms located at topological distances 6 and 3. Based on the conclusion given in the QSAR analysis, a new compound with possible great activity was proposed.

Structure-activity relationships of selected phenazines against Mycobacterium leprae in vitro.

PubMed Central

Franzblau, S G; O'Sullivan, J F

1988-01-01

Structure-activity relationships of phenazines against Mycobacterium leprae were investigated by using an in vitro radiorespirometric assay. In general, activity in ascending order was observed in compounds containing no chlorine atoms, a monochlorinated phenazine nucleus, and chlorines in the para positions of both the anilino and phenyl rings. The most active compounds contained a 2,2,6,6-tetramethylpiperidine substitution at the imino nitrogen. Most of these chlorinated phenazines were considerably more active in vitro than clofazimine (B663). PMID:3056241

The recombinant expression and activity detection of MAF-1 fusion protein.

PubMed

Fu, Ping; Wu, Jianwei; Gao, Song; Guo, Guo; Zhang, Yong; Liu, Jian

2015-10-01

This study establishes the recombinant expression system of MAF-1 (Musca domestica antifungal peptide-1) and demonstrates the antifungal activity of the expression product and shows the relationship between biological activity and structure. The gene segments on mature peptide part of MAF-1 were cloned, based on the primers designed according to the cDNA sequence of MAF-1. We constructed the recombinant prokaryotic expression plasmid using prokaryotic expression vector (pET-28a(+)) and converted it to the competent cell of BL21(DE3) to gain recombinant MAF-1 fusion protein with His tag sequence through purifying affinity chromatographic column of Ni-NTA. To conduct the Western Blotting test, recombinant MAF-1 fusion protein was used to produce the polyclonal antibody of rat. The antifungal activity of the expression product was detected using Candida albicans (ATCC10231) as the indicator. The MAF-1 recombinant fusion protein was purified to exhibit obvious antifungal activity, which lays the foundation for the further study of MAF-1 biological activity, the relationship between structure and function, as well as control of gene expression.

Discovery, synthesis, and structure-activity relationships of 20(S)-protopanaxadiol (PPD) derivatives as a novel class of AMPKα2β1γ1 activators.

PubMed

Liu, Junhua; Chen, Dakai; Liu, Peng; He, Mengna; Li, Jia; Li, Jingya; Hu, Lihong

2014-05-22

Adenosine 5'-monophosphate-activated protein kinase (AMPK) has been demonstrated as a promising drug target due to its regulatory function in glucose and lipid metabolism. 20(S)-protopanoxadiol (PPD) was firstly identified from high throughput screening as a small molecule activator of AMPK subtype α2β1γ1. In order to enhance its potency on AMPK, a series of PPD derivatives were synthesized and evaluated. Structure-activity relationship study showed that the amine derivatives at the 24-position (groups I-VI) can improve the potency (EC50: 0.7-2.3 μM) and efficacy (fold: 2.5-3.8). Among them, compounds 12 and 13 exhibited the best potency (EC50: 1.2 and 0.7 μM) and efficacy (fold: 3.7 and 3.8). Further study suggested the mechanism of AMPK activation may functioned at the allosteric position, resulting the inhibition of the lipid synthesis in HepG2 cell model. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Aconitum and Delphinium sp. Alkaloids as Antagonist Modulators of Voltage-Gated Na+ Channels. AM1/DFT Electronic Structure Investigations and QSAR Studies

PubMed Central

Turabekova, Malakhat A.; Rasulev, Bakhtiyor F.; Levkovich, Mikhail G.; Abdullaev, Nasrulla D.; Leszczynski, Jerzy

2015-01-01

Early pharmacological studies of Aconitum and Delphinium sp. alkaloids suggested that these neurotoxins act at site 2 of voltage-gated Na+ channel and allosterically modulate its function. Understanding structural requirements for these compounds to exhibit binding activity at voltage-gated Na+ channel has been important in various fields. This paper reports quantum-chemical studies and quantitative structure-activity relationships (QSARs) based on a total of 65 natural alkaloids from two plant species, which includes both blockers and openers of sodium ion channel. A series of 18 antagonist alkaloids (9 blockers and 9 openers) have been studied using AM1 and DFT computational methods in order to reveal their structure-activity (structure-toxicity) relationship at electronic level. An examination of frontier orbitals obtained for ground and protonated forms of the compounds revealed that HOMOs and LUMOs were mainly represented by nitrogen atom and benzyl/benzoylester orbitals with –OH and –OCOCH3 contributions. The results obtained from this research have confirmed the experimental findings suggesting that neurotoxins acting at type 2 receptor site of voltage-dependent sodium channel are activators and blockers with common structural features and differ only in efficacy. The energetic tendency of HOMO-LUMO energy gap can probably distinguish activators and blockers that have been observed. Genetic Algorithm with Multiple Linear Regression Analysis (GA-MLRA) technique was also applied for the generation of two-descriptor QSAR models for the set of 65 blockers. Additionally to the computational studies, the HOMO-LUMO gap descriptor in each obtained QSAR model has confirmed the crucial role of charge transfer in receptor-ligand interactions. A number of other descriptors such as logP, IBEG, nNH2, nHDon, nCO have been selected as complementary ones to LUMO and their role in activity alteration has also been discussed. PMID:18201930

Self-efficacy and pain acceptance as mediators of the relationship between pain and performance of valued life activities in women and men with rheumatoid arthritis.

PubMed

Ahlstrand, Inger; Vaz, Sharmila; Falkmer, Torbjörn; Thyberg, Ingrid; Björk, Mathilda

2017-06-01

To study whether personal factors (self-efficacy and pain acceptance) mediate the relationship between pain and performance of valued life activities in persons with rheumatoid arthritis. Persons with rheumatoid arthritis for at least four years ( n = 737; 73% women) answered a questionnaire measuring self-efficacy, pain acceptance, performance of valued life activities, and self-rated pain. Relationships among these constructs were explored using univariate and multivariate analyses. Structural equation modelling was then used to examine the mediational role of personal factors on the relationship between pain and performance of valued life activities. A direct negative association between pain and performance of valued life activities was identified ( Beta = .34, P < .001). This suggests that people with rheumatoid arthritis who had higher levels of pain has increased difficulties in performing valued life activities. Self-efficacy and activity engagement component of pain acceptance mediated the relationship between pain and performance of valued life activities, however the pain willingness component of pain acceptance did not influence participation in valued life activities. These findings highlight the importance of considering personal factors, such as pain acceptance and self-efficacy, in facilitating participation in valued life activities.

Comparative Analysis of Predictive Models for Liver Toxicity Using ToxCast Assays and Quantitative Structure-Activity Relationships (MCBIOS)

EPA Science Inventory

Comparative Analysis of Predictive Models for Liver Toxicity Using ToxCast Assays and Quantitative Structure-Activity Relationships Jie Liu1,2, Richard Judson1, Matthew T. Martin1, Huixiao Hong3, Imran Shah1 1National Center for Computational Toxicology (NCCT), US EPA, RTP, NC...

Deep Eutectic Solvents as Convenient Media for Synthesis of Novel Coumarinyl Schiff Bases and Their QSAR Studies.

PubMed

Molnar, Maja; Komar, Mario; Brahmbhatt, Harshad; Babić, Jurislav; Jokić, Stela; Rastija, Vesna

2017-09-05

Deep eutectic solvents, as green and environmentally friendly media, were utilized in the synthesis of novel coumarinyl Schiff bases. Novel derivatives were synthesized from 2-((4-methyl-2-oxo-2 H -chromen-7-yl)oxy)acetohydrazide and corresponding aldehyde in choline chloride:malonic acid (1:1) based deep eutectic solvent. In these reactions, deep eutectic solvent acted as a solvent and catalyst as well. Novel Schiff bases were synthesized in high yields (65-75%) with no need for further purification, and their structures were confirmed by mass spectra, ¹H and 13 C NMR. Furthermore, their antioxidant activity was determined and compared to antioxidant activity of previously synthesized derivatives, thus investigating their structure-activity relationship utilizing quantitative structure-activity relationship QSAR studies. Calculation of molecular descriptors has been performed by DRAGON software. The best QSAR model ( R tr = 0.636; R ext = 0.709) obtained with three descriptors ( MATS3m , Mor22u , Hy ) implies that the pairs of atoms higher mass at the path length 3, three-dimensional arrangement of atoms at scattering parameter s = 21 Å - ¹, and higher number of hydrophilic groups (-OH, -NH) enhanced antioxidant activity. Electrostatic potential surface of the most active compounds showed possible regions for donation of electrons to 1,1-diphenyl-2-picryhydrazyl (DPPH) radicals.

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.

Insight into the structural requirements of aminopyrimidine derivatives for good potency against both purified enzyme and whole cells of M. tuberculosis: combination of HQSAR, CoMSIA, and MD simulation studies.

PubMed

Punkvang, Auradee; Hannongbua, Supa; Saparpakorn, Patchreenart; Pungpo, Pornpan

2016-05-01

The Mycobacterium tuberculosis protein kinase B (PknB) is critical for growth and survival of M. tuberculosis within the host. The series of aminopyrimidine derivatives show impressive activity against PknB (IC50 < .5 μM). However, most of them show weak or no cellular activity against M. tuberculosis (MIC > 63 μM). Consequently, the key structural features related to activity against of both PknB and M. tuberculosis need to be investigated. Here, two- and three-dimensional quantitative structure-activity relationship (2D and 3D QSAR) analyses combined with molecular dynamics (MD) simulations were employed with the aim to evaluate these key structural features of aminopyrimidine derivatives. Hologram quantitative structure-activity relationship (HQSAR) and CoMSIA models constructed from IC50 and MIC values of aminopyrimidine compounds could establish the structural requirements for better activity against of both PknB and M. tuberculosis. The NH linker and the R1 substituent of the template compound are not only crucial for the biological activity against PknB but also for the biological activity against M. tuberculosis. Moreover, the results obtained from MD simulations show that these moieties are the key fragments for binding of aminopyrimidine compounds in PknB. The combination of QSAR analysis and MD simulations helps us to provide a structural concept that could guide future design of PknB inhibitors with improved potency against both the purified enzyme and whole M. tuberculosis cells.

Partitioning and lipophilicity in quantitative structure-activity relationships.

PubMed Central

Dearden, J C

1985-01-01

The history of the relationship of biological activity to partition coefficient and related properties is briefly reviewed. The dominance of partition coefficient in quantitation of structure-activity relationships is emphasized, although the importance of other factors is also demonstrated. Various mathematical models of in vivo transport and binding are discussed; most of these involve partitioning as the primary mechanism of transport. The models describe observed quantitative structure-activity relationships (QSARs) well on the whole, confirming that partitioning is of key importance in in vivo behavior of a xenobiotic. The partition coefficient is shown to correlate with numerous other parameters representing bulk, such as molecular weight, volume and surface area, parachor and calculated indices such as molecular connectivity; this is especially so for apolar molecules, because for polar molecules lipophilicity factors into both bulk and polar or hydrogen bonding components. The relationship of partition coefficient to chromatographic parameters is discussed, and it is shown that such parameters, which are often readily obtainable experimentally, can successfully supplant partition coefficient in QSARs. The relationship of aqueous solubility with partition coefficient is examined in detail. Correlations are observed, even with solid compounds, and these can be used to predict solubility. The additive/constitutive nature of partition coefficient is discussed extensively, as are the available schemes for the calculation of partition coefficient. Finally the use of partition coefficient to provide structural information is considered. It is shown that partition coefficient can be a valuable structural tool, especially if the enthalpy and entropy of partitioning are available. PMID:3905374

Engineering Cu surfaces for the electrocatalytic conversion of CO2: Controlling selectivity toward oxygenates and hydrocarbons

PubMed Central

Hahn, Christopher; Hatsukade, Toru; Kim, Youn-Geun; Vailionis, Arturas; Baricuatro, Jack H.; Higgins, Drew C.; Nitopi, Stephanie A.; Soriaga, Manuel P.; Jaramillo, Thomas F.

2017-01-01

In this study we control the surface structure of Cu thin-film catalysts to probe the relationship between active sites and catalytic activity for the electroreduction of CO2 to fuels and chemicals. Here, we report physical vapor deposition of Cu thin films on large-format (∼6 cm2) single-crystal substrates, and confirm epitaxial growth in the <100>, <111>, and <751> orientations using X-ray pole figures. To understand the relationship between the bulk and surface structures, in situ electrochemical scanning tunneling microscopy was conducted on Cu(100), (111), and (751) thin films. The studies revealed that Cu(100) and (111) have surface adlattices that are identical to the bulk structure, and that Cu(751) has a heterogeneous kinked surface with (110) terraces that is closely related to the bulk structure. Electrochemical CO2 reduction testing showed that whereas both Cu(100) and (751) thin films are more active and selective for C–C coupling than Cu(111), Cu(751) is the most selective for >2e− oxygenate formation at low overpotentials. Our results demonstrate that epitaxy can be used to grow single-crystal analogous materials as large-format electrodes that provide insights on controlling electrocatalytic activity and selectivity for this reaction. PMID:28533377

Evaluating a Model of Youth Physical Activity

ERIC Educational Resources Information Center

Heitzler, Carrie D.; Lytle, Leslie A.; Erickson, Darin J.; Barr-Anderson, Daheia; Sirard, John R.; Story, Mary

2010-01-01

Objective: To explore the relationship between social influences, self-efficacy, enjoyment, and barriers and physical activity. Methods: Structural equation modeling examined relationships between parent and peer support, parent physical activity, individual perceptions, and objectively measured physical activity using accelerometers among a…

Perovskite oxides: Oxygen electrocatalysis and bulk structure

NASA Technical Reports Server (NTRS)

Carbonio, R. E.; Fierro, C.; Tryk, D.; Scherson, D.; Yeager, Ernest

1987-01-01

Perovskite type oxides were considered for use as oxygen reduction and generation electrocatalysts in alkaline electrolytes. Perovskite stability and electrocatalytic activity are studied along with possible relationships of the latter with the bulk solid state properties. A series of compounds of the type LaFe(x)Ni1(-x)O3 was used as a model system to gain information on the possible relationships between surface catalytic activity and bulk structure. Hydrogen peroxide decomposition rate constants were measured for these compounds. Ex situ Mossbauer effect spectroscopy (MES), and magnetic susceptibility measurements were used to study the solid state properties. X ray photoelectron spectroscopy (XPS) was used to examine the surface. MES has indicated the presence of a paramagnetic to magnetically ordered phase transition for values of x between 0.4 and 0.5. A correlation was found between the values of the MES isomer shift and the catalytic activity for peroxide decomposition. Thus, the catalytic activity can be correlated to the d-electron density for the transition metal cations.

Perovskite-type oxides - Oxygen electrocatalysis and bulk structure

NASA Technical Reports Server (NTRS)

Carbonio, R. E.; Fierro, C.; Tryk, D.; Scherson, D.; Yeager, E.

1988-01-01

Perovskite type oxides were considered for use as oxygen reduction and generation electrocatalysts in alkaline electrolytes. Perovskite stability and electrocatalytic activity are studied along with possible relationships of the latter with the bulk solid state properties. A series of compounds of the type LaFe(x)Ni1(-x)O3 was used as a model system to gain information on the possible relationships between surface catalytic activity and bulk structure. Hydrogen peroxide decomposition rate constants were measured for these compounds. Ex situ Mossbauer effect spectroscopy (MES), and magnetic susceptibility measurements were used to study the solid state properties. X ray photoelectron spectroscopy (XPS) was used to examine the surface. MES has indicated the presence of a paramagnetic to magnetically ordered phase transition for values of x between 0.4 and 0.5. A correlation was found between the values of the MES isomer shift and the catalytic activity for peroxide decomposition. Thus, the catalytic activity can be correlated to the d-electron density for the transition metal cations.

Development of Novel Repellents Using Structure - Activity Modeling of Compounds in the USDA Archival Database

DTIC Science & Technology

2011-01-01

used in efforts to develop QSAR models. Measurement of Repellent Efficacy Screening for Repellency of Compounds with Unknown Toxicology In screening...CPT) were used to develop Quantitative Structure Activity Relationship ( QSAR ) models to predict repellency. Successful prediction of novel...acylpiperidine QSAR models employed 4 descriptors to describe the relationship between structure and repellent duration. The ANN model of the carboxamides did not

Hot and Spicy versus Cool and Minty as an Example of Organic Structure-Activity Relationships

NASA Astrophysics Data System (ADS)

Kimbrough, Doris R.

1997-07-01

There are two classes of substances that activate neural receptors that are involved in temperature perception. Structures of substances found in spices and food that we normally associate with "hot" (or spicy) and "cool" (or minty) flavors are presented and discussed. Functional group similarities within the two groups provide an interesting example of the relationship between molecular structure and molecular function in organic chemistry.

Toll-like receptor 4-related immunostimulatory polysaccharides: Primary structure, activity relationships, and possible interaction models.

PubMed

Zhang, Xiaorui; Qi, Chunhui; Guo, Yan; Zhou, Wenxia; Zhang, Yongxiang

2016-09-20

Toll-like receptor (TLR) 4 is an important polysaccharide receptor; however, the relationships between the structures and biological activities of TLR4 and polysaccharides remain unknown. Many recent findings have revealed the primary structure of TLR4/MD-2-related polysaccharides, and several three-dimensional structure models of polysaccharide-binding proteins have been reported; and these models provide insights into the mechanisms through which polysaccharides interact with TLR4. In this review, we first discuss the origins of polysaccharides related to TLR4, including polysaccharides from higher plants, fungi, bacteria, algae, and animals. We then briefly describe the glucosidic bond types of TLR4-related heteroglycans and homoglycans and describe the typical molecular weights of TLR4-related polysaccharides. The primary structures and activity relationships of polysaccharides with TLR4/MD-2 are also discussed. Finally, based on the existing interaction models of LPS with TLR4/MD-2 and linear polysaccharides with proteins, we provide insights into the possible interaction models of polysaccharide ligands with TLR4/MD-2. To our knowledge, this review is the first to summarize the primary structures and activity relationships of TLR4-related polysaccharides and the possible mechanisms of interaction for TLR4 and TLR4-related polysaccharides. Copyright © 2016 Elsevier Ltd. All rights reserved.

Novel diamide-based inhibitors of IMPDH.

PubMed

Gu, Henry H; Iwanowicz, Edwin J; Guo, Junqing; Watterson, Scott H; Shen, Zhongqi; Pitts, William J; Dhar, T G Murali; Fleener, Catherine A; Rouleau, Katherine; Sherbina, N Z; Witmer, Mark; Tredup, Jeffrey; Hollenbaugh, Diane

2002-05-06

A series of novel amide-based small molecule inhibitors of inosine monophosphate dehydrogenase is described. The synthesis and the structure-activity relationships (SARs) derived from in vitro studies are presented.

Quantitative structure-activity relationships studies of CCR5 inhibitors and toxicity of aromatic compounds using gene expression programming.

PubMed

Shi, Weimin; Zhang, Xiaoya; Shen, Qi

2010-01-01

Quantitative structure-activity relationship (QSAR) study of chemokine receptor 5 (CCR5) binding affinity of substituted 1-(3,3-diphenylpropyl)-piperidinyl amides and ureas and toxicity of aromatic compounds have been performed. The gene expression programming (GEP) was used to select variables and produce nonlinear QSAR models simultaneously using the selected variables. In our GEP implementation, a simple and convenient method was proposed to infer the K-expression from the number of arguments of the function in a gene, without building the expression tree. The results were compared to those obtained by artificial neural network (ANN) and support vector machine (SVM). It has been demonstrated that the GEP is a useful tool for QSAR modeling. Copyright 2009 Elsevier Masson SAS. All rights reserved.

Aerobic Fitness Linked to Cortical Brain Development in Adolescent Males: Preliminary Findings Suggest a Possible Role of BDNF Genotype.

PubMed

Herting, Megan M; Keenan, Madison F; Nagel, Bonnie J

2016-01-01

Aerobic exercise has been shown to impact brain structure and cognition in children and adults. Exercise-induced activation of a growth protein known as brain derived neurotrophic factor (BDNF) is thought to contribute to such relationships. To date, however, no study has examined how aerobic fitness relates to cortical brain structure during development and if BDNF genotype moderates these relationships. Using structural magnetic resonance imaging (MRI) and FreeSurfer, the current study examined how aerobic fitness relates to volume, thickness, and surface area in 34 male adolescents, 15 to 18 years old. Moreover, we examined if the val66met BDNF genotype moderated these relationships. We hypothesized that aerobic fitness would relate to greater thickness and volumes in frontal, parietal, and motor regions, and that these relationships would be less robust in individuals carrying a Met allele, since this genotype leads to lower BDNF expression. We found that aerobic fitness positively related to right rostral middle frontal cortical volume in all adolescents. However, results also showed BDNF genotype moderated the relationship between aerobic fitness and bilateral medial precuneus surface area, with a positive relationship seen in individuals with the Val/Val allele, but no relationship detected in those adolescents carrying a Met allele. Lastly, using self-reported levels of aerobic activity, we found that higher-fit adolescents showed larger right medial pericalcarine, right cuneus and left precuneus surface areas as compared to their low-fit peers. Our findings suggest that aerobic fitness is linked to cortical brain development in male adolescents, and that more research is warranted to determine how an individual's genes may influence these relationships.

Aerobic Fitness Linked to Cortical Brain Development in Adolescent Males: Preliminary Findings Suggest a Possible Role of BDNF Genotype

PubMed Central

Herting, Megan M.; Keenan, Madison F.; Nagel, Bonnie J.

2016-01-01

Aerobic exercise has been shown to impact brain structure and cognition in children and adults. Exercise-induced activation of a growth protein known as brain derived neurotrophic factor (BDNF) is thought to contribute to such relationships. To date, however, no study has examined how aerobic fitness relates to cortical brain structure during development and if BDNF genotype moderates these relationships. Using structural magnetic resonance imaging (MRI) and FreeSurfer, the current study examined how aerobic fitness relates to volume, thickness, and surface area in 34 male adolescents, 15 to 18 years old. Moreover, we examined if the val66met BDNF genotype moderated these relationships. We hypothesized that aerobic fitness would relate to greater thickness and volumes in frontal, parietal, and motor regions, and that these relationships would be less robust in individuals carrying a Met allele, since this genotype leads to lower BDNF expression. We found that aerobic fitness positively related to right rostral middle frontal cortical volume in all adolescents. However, results also showed BDNF genotype moderated the relationship between aerobic fitness and bilateral medial precuneus surface area, with a positive relationship seen in individuals with the Val/Val allele, but no relationship detected in those adolescents carrying a Met allele. Lastly, using self-reported levels of aerobic activity, we found that higher-fit adolescents showed larger right medial pericalcarine, right cuneus and left precuneus surface areas as compared to their low-fit peers. Our findings suggest that aerobic fitness is linked to cortical brain development in male adolescents, and that more research is warranted to determine how an individual’s genes may influence these relationships. PMID:27445764

Physical activity and cardiac function in the oldest old.

PubMed

Stessman-Lande, Irit; Jacobs, Jeremy M; Gilon, Dan; Leibowitz, David

2012-02-01

The relationship of physical activity (PA) and cardiac function in the oldest old remains unclear. The objective of this study was to evaluate the relationship between PA and cardiac structure and function, in the oldest old. Subjects were recruited from the Jerusalem Longitudinal Cohort Study that was initiated in 1990 and has followed an age homogeneous cohort of Jerusalem residents born in 1920-1921. A total of 496 of the subjects from the most recent set of data collection in 2005-2006 underwent echocardiography at their place of residence in addition to structured interviews and physical examination. Standard echocardiographic assessment of cardiac structure and function including ejection fraction (EF) and diastolic function as assessed by E:E' measurements was performed. PA was defined as a dichotomous (≥4 hr of light exercise weekly) and as a categorical variable (<4 hr weekly/4 hours weekly/at least 1 hr daily/sport at least twice weekly). On bivariate analysis, mean EF was lower among sedentary versus active women (55.5%±8.5% vs. 58.4%±8.3, p=0.021). No other significant differences were observed between sedentary and active subjects, for either systolic or diastolic function. After adjusting for sex, education, diabetes, ischemic heart disease, hypertension, dependence in activities of daily living, and body mass index (BMI), no significant associations were found between systolic or diastolic function, or left ventricular structure and PA. Gender-specific analyses yielded similar findings. Our study of the oldest old did not demonstrate an association between PA and cardiac structure or function.

Educational Challenges in Toxicology.

ERIC Educational Resources Information Center

Dixon, Robert L.

1984-01-01

Issues and topics related to educational challenges in toxicology at all levels are discussed. They include public awareness and understanding, general approach to toxicology, quality structure-activity relationships, epidemiological studies, quantification of risk, and the types of toxicants studied. (JN)

Structure-activity relationships among derivatives of dicarboxylic acid esters of tropine.

PubMed

Gyermek, Laszlo

2002-10-01

Several categories of neuromuscular blocking bisquaternary tropine and tropane derivatives were synthesized and studied in the past five decades, mainly with the purpose of arriving at meaningful information about structure-activity relationships. Such a structure-activity relationship database is important in the development of new muscle relaxants with improved pharmacological characteristics. Although quaternary tropine diesters were explored since 1952, most of them were developed in the last decade. Over 250 such agents are being reviewed here. The skeleton of the majority of them consists of two tropines, connected through their 3-OH group with various dicarboxylic acid ester linkages and quaternized by several mostly di- and trisubstituted benzyl groups. The significance of changing the quaternizing group; the diester linker; and, to a smaller extent, the substituents and their steric orientation on the tropane ring and some alterations of the tropane ring itself have been explored in in vivo experiments on anesthetized rats. Di- or trisubstituted alkoxy and/or acyloxybenzyl quaternaries of certain tropinyl diesters, e.g., glutaryl, fumaryl, and cyclobutane-1,2-dicarboxylyl, showed an optimal profile with respect to desirable neuromuscular blocking actions and side effects, which was confirmed on other experimental animal species. The details of the structural changes toward obtaining new ultrashort-acting nondepolarizing muscle relaxants are discussed.

Solution structures, dynamics, and ice growth inhibitory activity of peptide fragments derived from an antarctic yeast protein.

PubMed

Shah, Syed Hussinien H; Kar, Rajiv K; Asmawi, Azren A; Rahman, Mohd Basyaruddin A; Murad, Abdul Munir A; Mahadi, Nor M; Basri, Mahiran; Rahman, Raja Noor Zaliha A; Salleh, Abu B; Chatterjee, Subhrangsu; Tejo, Bimo A; Bhunia, Anirban

2012-01-01

Exotic functions of antifreeze proteins (AFP) and antifreeze glycopeptides (AFGP) have recently been attracted with much interest to develop them as commercial products. AFPs and AFGPs inhibit ice crystal growth by lowering the water freezing point without changing the water melting point. Our group isolated the Antarctic yeast Glaciozyma antarctica that expresses antifreeze protein to assist it in its survival mechanism at sub-zero temperatures. The protein is unique and novel, indicated by its low sequence homology compared to those of other AFPs. We explore the structure-function relationship of G. antarctica AFP using various approaches ranging from protein structure prediction, peptide design and antifreeze activity assays, nuclear magnetic resonance (NMR) studies and molecular dynamics simulation. The predicted secondary structure of G. antarctica AFP shows several α-helices, assumed to be responsible for its antifreeze activity. We designed several peptide fragments derived from the amino acid sequences of α-helical regions of the parent AFP and they also showed substantial antifreeze activities, below that of the original AFP. The relationship between peptide structure and activity was explored by NMR spectroscopy and molecular dynamics simulation. NMR results show that the antifreeze activity of the peptides correlates with their helicity and geometrical straightforwardness. Furthermore, molecular dynamics simulation also suggests that the activity of the designed peptides can be explained in terms of the structural rigidity/flexibility, i.e., the most active peptide demonstrates higher structural stability, lower flexibility than that of the other peptides with lower activities, and of lower rigidity. This report represents the first detailed report of downsizing a yeast AFP into its peptide fragments with measurable antifreeze activities.

Solution Structures, Dynamics, and Ice Growth Inhibitory Activity of Peptide Fragments Derived from an Antarctic Yeast Protein

PubMed Central

Asmawi, Azren A.; Rahman, Mohd Basyaruddin A.; Murad, Abdul Munir A.; Mahadi, Nor M.; Basri, Mahiran; Rahman, Raja Noor Zaliha A.; Salleh, Abu B.; Chatterjee, Subhrangsu; Tejo, Bimo A.; Bhunia, Anirban

2012-01-01

Exotic functions of antifreeze proteins (AFP) and antifreeze glycopeptides (AFGP) have recently been attracted with much interest to develop them as commercial products. AFPs and AFGPs inhibit ice crystal growth by lowering the water freezing point without changing the water melting point. Our group isolated the Antarctic yeast Glaciozyma antarctica that expresses antifreeze protein to assist it in its survival mechanism at sub-zero temperatures. The protein is unique and novel, indicated by its low sequence homology compared to those of other AFPs. We explore the structure-function relationship of G. antarctica AFP using various approaches ranging from protein structure prediction, peptide design and antifreeze activity assays, nuclear magnetic resonance (NMR) studies and molecular dynamics simulation. The predicted secondary structure of G. antarctica AFP shows several α-helices, assumed to be responsible for its antifreeze activity. We designed several peptide fragments derived from the amino acid sequences of α-helical regions of the parent AFP and they also showed substantial antifreeze activities, below that of the original AFP. The relationship between peptide structure and activity was explored by NMR spectroscopy and molecular dynamics simulation. NMR results show that the antifreeze activity of the peptides correlates with their helicity and geometrical straightforwardness. Furthermore, molecular dynamics simulation also suggests that the activity of the designed peptides can be explained in terms of the structural rigidity/flexibility, i.e., the most active peptide demonstrates higher structural stability, lower flexibility than that of the other peptides with lower activities, and of lower rigidity. This report represents the first detailed report of downsizing a yeast AFP into its peptide fragments with measurable antifreeze activities. PMID:23209600

Relationships Between Watershed Emergy Flow and Coastal New England Salt Marsh Structure, Function, and Condition

EPA Science Inventory

This study evaluated the link between watershed activities and salt marsh structure, function, and condition using spatial emergy flow density (areal empower density) in the watershed and field data from 10 tidal salt marshes in Narragansett Bay, RI. The field-collected data wer...

Novel approaches to determine contractile function of the isolated adult zebrafish ventricular cardiac myocyte.

PubMed

Dvornikov, Alexey V; Dewan, Sukriti; Alekhina, Olga V; Pickett, F Bryan; de Tombe, Pieter P

2014-05-01

The zebrafish (Danio rerio) has been used extensively in cardiovascular biology, but mainly in the study of heart development. The relative ease of its genetic manipulation may indicate the suitability of this species as a cost-effective model system for the study of cardiac contractile biology. However, whether the zebrafish heart is an appropriate model system for investigations pertaining to mammalian cardiac contractile structure-function relationships remains to be resolved. Myocytes were isolated from adult zebrafish hearts by enzymatic digestion, attached to carbon rods, and twitch force and intracellular Ca(2+) were measured. We observed the modulation of twitch force, but not of intracellular Ca(2+), by both extracellular [Ca(2+)] and sarcomere length. In permeabilized cells/myofibrils, we found robust myofilament length-dependent activation. Moreover, modulation of myofilament activation-relaxation and force redevelopment kinetics by varied Ca(2+) activation levels resembled that found previously in mammalian myofilaments. We conclude that the zebrafish is a valid model system for the study of cardiac contractile structure-function relationships.

Evaluation and structure-activity relationship analysis of a new series of arylnaphthalene lignans as potential anti-tumor agents.

PubMed

Luo, Jiaoyang; Hu, Yichen; Kong, Weijun; Yang, Meihua

2014-01-01

Arylnaphthalene lignan lactones have attracted considerable interest because of their anti-tumor and anti-hyperlipidimic activities. However, to our knowledge, few studies have explored the effects of these compounds on human leukemia cell lines. In this study, five arylnaphthalene lignans including 6'-hydroxy justicidin A (HJA), 6'-hydroxy justicidin B (HJB), justicidin B (JB), chinensinaphthol methyl ether (CME) and Taiwanin E methyl ether (TEME) were isolated from Justicia procumbens and their effects on the proliferation and apoptosis of the human leukemia K562 cell line were investigated then used to assess structure-activity relationships. To achieve these aims, cytotoxicity was assayed using the MTT assay, while intracellular SOD activity was detected using the SOD Activity Assay kit. Apoptosis was measured by both the using a cycle TEST PLUS DNA reagent kit as well as the FITC Annexin V apoptosis detection kit in combination with flow cytometry. Activation of caspase-mediated apoptosis was evaluated using a FITC active Caspase-3 apoptosis kit and flow cytometry. The results indicated that HJB, HJA and JB significantly inhibited the growth of K562 cells by decreasing both proliferation and SOD activity and inducing apoptosis. The sequence of anti-proliferative activity induced by the five tested arylnaphthalenes by decreasing strength was HJB > HJA > JB > CME > TEME. HJB, HJA and JB also decreased SOD activity and induced apoptosis in a dose-dependent manner. Activation of caspase-3 further indicated that HJB, HJA and JB induced caspase-dependent intrinsic and/or extrinsic apoptosis pathways. Together, these assays suggest that arylnaphthalene lignans derived from Justicia procumbens induce apoptosis to varying degrees, through a caspase-dependent pathway in human leukemia K562 cells. Furthermore, analysis of structure-activity relationships suggest that hydroxyl substitution at C-1 and C-6' significantly increased the antiproliferative activity of arylnaphthalene lignans while a methoxyl at C-1 significantly decreased the effect.

Defining the molecular structure of teixobactin analogues and understanding their role in antibacterial activities.

PubMed

Parmar, Anish; Prior, Stephen H; Iyer, Abhishek; Vincent, Charlotte S; Van Lysebetten, Dorien; Breukink, Eefjan; Madder, Annemieke; Taylor, Edward J; Singh, Ishwar

2017-02-07

The discovery of the highly potent antibiotic teixobactin, which kills the bacteria without any detectable resistance, has stimulated interest in its structure-activity relationship. However, a molecular structure-activity relationship has not been established so far for teixobactin. Moreover, the importance of the individual amino acids in terms of their l/d configuration and their contribution to the molecular structure and biological activity are still unknown. For the first time, we have defined the molecular structure of seven teixobactin analogues through the variation of the d/l configuration of its key residues, namely N-Me-d-Phe, d-Gln, d-allo-Ile and d-Thr. Furthermore, we have established the role of the individual d amino acids and correlated this with the molecular structure and biological activity. Through extensive NMR and structural calculations, including molecular dynamics simulations, we have revealed the residues for maintaining a reasonably unstructured teixobactin which is imperative for biological activity.

Noncoded amino acids in protein engineering: Structure-activity relationship studies of hirudin-thrombin interaction.

PubMed

De Filippis, Vincenzo; Acquasaliente, Laura; Pontarollo, Giulia; Peterle, Daniele

2018-01-01

The advent of recombinant DNA technology allowed to site-specifically insert, delete, or mutate almost any amino acid in a given protein, significantly improving our knowledge of protein structure, stability, and function. Nevertheless, a quantitative description of the physical and chemical basis that makes a polypeptide chain to efficiently fold into a stable and functionally active conformation is still elusive. This mainly originates from the fact that nature combined, in a yet unknown manner, different properties (i.e., hydrophobicity, conformational propensity, polarizability, and hydrogen bonding capability) into the 20 standard natural amino acids, thus making difficult, if not impossible, to univocally relate the change in protein stability or function to the alteration of physicochemical properties caused by amino acid exchange(s). In this view, incorporation of noncoded amino acids with tailored side chains, allowing to finely tune the structure at a protein site, would facilitate to dissect the effects of a given mutation in terms of one or a few physicochemical properties, thus much expanding the scope of physical organic chemistry in the study of proteins. In this review, relevant applications from our laboratory will be presented on the use of noncoded amino acids in structure-activity relationships studies of hirudin binding to thrombin. © 2017 International Union of Biochemistry and Molecular Biology, Inc.

Further evaluation of quantitative structure--activity relationship models for the prediction of the skin sensitization potency of selected fragrance allergens.

PubMed

Patlewicz, Grace Y; Basketter, David A; Pease, Camilla K Smith; Wilson, Karen; Wright, Zoe M; Roberts, David W; Bernard, Guillaume; Arnau, Elena Giménez; Lepoittevin, Jean-Pierre

2004-02-01

Fragrance substances represent a very diverse group of chemicals; a proportion of them are associated with the ability to cause allergic reactions in the skin. Efforts to find substitute materials are hindered by the need to undertake animal testing for determining both skin sensitization hazard and potency. One strategy to avoid such testing is through an understanding of the relationships between chemical structure and skin sensitization, so-called structure-activity relationships. In recent work, we evaluated 2 groups of fragrance chemicals -- saturated aldehydes and alpha,beta-unsaturated aldehydes. Simple quantitative structure-activity relationship (QSAR) models relating the EC3 values [derived from the local lymph node assay (LLNA)] to physicochemical properties were developed for both sets of aldehydes. In the current study, we evaluated an additional group of carbonyl-containing compounds to test the predictive power of the developed QSARs and to extend their scope. The QSAR models were used to predict EC3 values of 10 newly selected compounds. Local lymph node assay data generated for these compounds demonstrated that the original QSARs were fairly accurate, but still required improvement. Development of these QSAR models has provided us with a better understanding of the potential mechanisms of action for aldehydes, and hence how to avoid or limit allergy. Knowledge generated from this work is being incorporated into new/improved rules for sensitization in the expert toxicity prediction system, deductive estimation of risk from existing knowledge (DEREK).

From bird's eye views to molecular communities: two-layered visualization of structure-activity relationships in large compound data sets

NASA Astrophysics Data System (ADS)

Kayastha, Shilva; Kunimoto, Ryo; Horvath, Dragos; Varnek, Alexandre; Bajorath, Jürgen

2017-11-01

The analysis of structure-activity relationships (SARs) becomes rather challenging when large and heterogeneous compound data sets are studied. In such cases, many different compounds and their activities need to be compared, which quickly goes beyond the capacity of subjective assessments. For a comprehensive large-scale exploration of SARs, computational analysis and visualization methods are required. Herein, we introduce a two-layered SAR visualization scheme specifically designed for increasingly large compound data sets. The approach combines a new compound pair-based variant of generative topographic mapping (GTM), a machine learning approach for nonlinear mapping, with chemical space networks (CSNs). The GTM component provides a global view of the activity landscapes of large compound data sets, in which informative local SAR environments are identified, augmented by a numerical SAR scoring scheme. Prioritized local SAR regions are then projected into CSNs that resolve these regions at the level of individual compounds and their relationships. Analysis of CSNs makes it possible to distinguish between regions having different SAR characteristics and select compound subsets that are rich in SAR information.

Structural complexities in the active layers of organic electronics.

PubMed

Lee, Stephanie S; Loo, Yueh-Lin

2010-01-01

The field of organic electronics has progressed rapidly in recent years. However, understanding the direct structure-function relationships between the morphology in electrically active layers and the performance of devices composed of these materials has proven difficult. The morphology of active layers in organic electronics is inherently complex, with heterogeneities existing across multiple length scales, from subnanometer to micron and millimeter range. A major challenge still facing the organic electronics community is understanding how the morphology across all of the length scales in active layers collectively determines the device performance of organic electronics. In this review we highlight experiments that have contributed to the elucidation of structure-function relationships in organic electronics and also point to areas in which knowledge of such relationships is still lacking. Such knowledge will lead to the ability to select active materials on the basis of their inherent properties for the fabrication of devices with prespecified characteristics.

Structure and biological activity of protopanaxatriol-type saponins from the roots of Panax notoginseng.

PubMed

Sun, Hongxiang; Yang, Zhigang; Ye, Yiping

2006-01-01

The further purification of the total saponins from the roots of Panax notoginseng by using ordinary and reversed-phase silica-gel, as well as Sephadex LH-20 chromatography afford seven adjuvant active protopanaxatriol-type saponins (PTS), ginsenosides-Rh1 (Rh1),-Rh4 (Rh4),-Rg1 (Rg1),-Re (Re), notoginsenosides-R1 (R1),-R2 (R2),-U (U). These saponins were evaluated for their haemolytic activities and adjuvant potentials on the cellular and humoral immune responses of ICR mice against ovalbumin (OVA). The effect of the substitution pattern of these PTS on their biological activities was investigated and structure-activity relationships were established. Among seven PTS, the haemolytic activity of Rh1 was higher than that of other six compounds (p<0.001) The HD50 values of Rh4 and U were significantly bigger than those of R2, Rg1 and Re (p<0.05 or p<0.01). Seven PTS could significantly increase the concanavalin A (Con A)-, lipopolysaccharide (LPS)- and OVA-induced splenocyte proliferation in the OVA-immunized mice (p<0.01 or p<0.001). The OVA-specific IgG, IgG1, IgG2a and IgG2b antibody levels in serum were also significantly enhanced by seven PTS compared with OVA control group (p<0.01 or p<0.001). The structure-activity relationship studies suggested that the number, the length and the position of sugar side chains, and the type of glucosyl group in the structure of PTS could not only affect their haemolytic activities and adjuvant potentials, but have significant effects on the nature of the immune responses. The information about this structure/function relationship might be useful for developing semisynthetic tetracyclic triterpenoid saponin derivatives with immunological adjuvant activity, as well as a reference to the distribution of the functional groups composing the saponin molecule.

The structure-activity relationships of mansonone F, a potent anti-MRSA sesquiterpenoid quinone: SAR studies on the C6 and C9 analogs.

PubMed

Suh, Young-Ger; Kim, Sun Nam; Shin, Dong-Yun; Hyun, Soon-Sil; Lee, Do-Sang; Min, Kyung-Hoon; Han, Sae Mi; Li, Funan; Choi, Eung-Chil; Choi, Seong-Hak

2006-01-01

For the systematic SAR study on mansonone F, a series of C6 and C9 analogs of mansonone F have been synthesized and their anti-MRSA activities were evaluated. Most of the analogs exhibited good or excellent anti-MRSA activities. In particular, the 6-n-butylmansonone F showed fourfold higher antibacterial activities compared to that of vancomycin.

Supporting Representational Competence in High School Biology with Computer-Based Biomolecular Visualizations

ERIC Educational Resources Information Center

Wilder, Anna; Brinkerhoff, Jonathan

2007-01-01

This study assessed the effectiveness of computer-based biomolecular visualization activities on the development of high school biology students' representational competence as a means of understanding and visualizing protein structure/function relationships. Also assessed were students' attitudes toward these activities. Sixty-nine students…

Identifying Metabolically Active Chemicals Using a Consensus Quantitative Structure Activity Relationship Model for Estrogen Receptor Binding

EPA Science Inventory

Traditional toxicity testing provides insight into the mechanisms underlying toxicological responses but requires a high investment in a large number of resources. The new paradigm of testing approaches involves rapid screening studies able to evaluate thousands of chemicals acro...

Structure-activity relationship of karrikin germination stimulants.

PubMed

Flematti, Gavin R; Scaffidi, Adrian; Goddard-Borger, Ethan D; Heath, Charles H; Nelson, David C; Commander, Lucy E; Stick, Robert V; Dixon, Kingsley W; Smith, Steven M; Ghisalberti, Emilio L

2010-08-11

Karrikins (2H-furo[2,3-c]pyran-2-ones) are potent smoke-derived germination promoters for a diverse range of plant species but, to date, their mode of action remains unknown. This paper reports the structure-activity relationship of numerous karrikin analogues to increase understanding of the key structural features of the molecule that are required for biological activity. The results demonstrate that modification at the C5 position is preferred over modification at the C3, C4, or C7 positions for retaining the highest bioactivity.

Youth participation in organized and informal sports activities across childhood and adolescence: exploring the relationships of motivational beliefs, developmental stage and gender.

PubMed

Dawes, Nickki Pearce; Vest, Andrea; Simpkins, Sandra

2014-08-01

Involvement in physically active pursuits, such as sports, contributes to achieving and maintaining good emotional and physical health. The central goal of this article was to examine the longitudinal relationships between participation (i.e., time spent in the activities) in organized and informal sports contexts and motivational beliefs, and factors that might impact these relationships, such as developmental stage and gender. The data for the current study were drawn from the childhood and beyond longitudinal study, which utilized a cohort sequential design with data collected on three cohorts across four waves. The current study sample included 986 European American youth (51 % female), who t were mostly from working- and middle-class families. Self-report questionnaires were used to collect data from the youth about their participation in sports and their motivational beliefs (i.e., value and perceptions of competence) about this activity. Structural equation modeling was used to examine the relationships between participation and motivational beliefs across childhood and adolescence. The results provide some support for a model of reciprocal relationships between participation and motivational beliefs in organized and informal sports activities. These relationships between participation and motivational beliefs did not vary significantly based on developmental stage or by gender. Overall, the findings suggest that participation in organized and informal sports contexts may be fostered by supporting the development of positive motivational beliefs about the activities across developmental periods.

Activation of Midbrain Structures by Associative Novelty and the Formation of Explicit Memory in Humans

ERIC Educational Resources Information Center

Schott, Bjorn H.; Sellner, Daniela B.; Lauer, Corinna-J.; Habib, Reza; Frey, Julietta U.; Guderian, Sebastian; Heinze, Hans-Jochen; Duzel, Emrah

2004-01-01

Recent evidence suggests a close functional relationship between memory formation in the hippocampus and dopaminergic neuromodulation originating in the ventral tegmental area and medial substantia nigra of the midbrain. Here we report midbrain activation in two functional MRI studies of visual memory in healthy young adults. In the first study,…

The Relationship of the Jenkins Activity Survey to Type A Behavior among Business Executives.

ERIC Educational Resources Information Center

Begley, Thomas M.; Boyd, David P.

1985-01-01

Examined the internal structure of the Jenkins Activity Survey. Results include identification of five factors, three of which are similar to factors identified in earlier studies, identification of a subset of items that show consistency across studies, and discovery that two scales are essentially the same in their defining items. (Author/BL)

The Influence of Joint Loading on Bone Marrow Lesions in the Knee: A Systematic Review With Meta-analysis.

PubMed

Beckwée, David; Vaes, Peter; Shahabpour, Maryam; Muyldermans, Ronald; Rommers, Nikki; Bautmans, Ivan

2015-12-01

Bone marrow lesions (BMLs) are considered as predictors of pain, disability, and structural progression of knee osteoarthritis. The relationship between knee loading and BMLs is not yet completely understood. To summarize the available evidence regarding the relationship between joint loading and the prevalence and progression of BMLs in the tibiofemoral joint. Meta-analysis. Three databases (PubMed, Web of Science, and The Cochrane Library) were systematically screened for studies encompassing BMLs and changes in knee loading. A methodological quality assessment was conducted, and a meta-analysis computing overall odds ratios (ORs) was performed where possible. A total of 29 studies involving 7641 participants were included. Mechanical loading was categorized as body weight and composition, compartmental load, structural lesion, and physical activity. High compartmental loads and structural lesions increased the risk for BMLs (overall ORs ranging from 1.56 [95% CI, 1.13-2.15] to 8.2 [95% CI, 4.4-15.1]; P = .006). Body weight increased the risk for BMLs to a lesser extent (overall OR, 1.03; 95% CI, 1.01-1.05; P = .007). Contradictory results for the effect of physical activity on BMLs were found. Augmented compartmental loads and structural lesions increased the risk of the presence or progression of BMLs. Body weight increased the risk for BMLs to a lesser extent. Contradictory results for the effect of physical activity on BMLs may be explained by a dose-response relationship, knee alignment, and structural lesions. It has been shown that unloading the knee temporarily may induce beneficial effects on osteoarthritis-related structural changes. Therefore, an early recognition of BMLs in the aging athlete's knee may provide information to counter the onset and aggravation of symptomatic knee osteoarthritis by reducing the knee load. © 2015 The Author(s).

A Mixed-Method Exploration of School Organizational and Social Relationship Factors That Influence Dropout-Decision Making in a Rural High School

ERIC Educational Resources Information Center

Farina, Andrea J.

2013-01-01

This explanatory mixed-method study explored the dropout phenomenon from an ecological perspective identifying the school organizational (academics, activities, structure) and social relationship (teachers, peers) factors that most significantly influence students' decisions to leave school prior to graduation at a rural high school in south…

Argumentation as a Lens to Examine Student Discourse in Peer-Led Guided Inquiry for College General Chemistry

NASA Astrophysics Data System (ADS)

Kulatunga, Ushiri Kumarihamy

This dissertation work entails three related studies on the investigation of Peer-Led Guided Inquiry student discourse in a General Chemistry I course through argumentation. The first study, Argumentation and participation patterns in general chemistry peer-led sessions, is focused on examining arguments and participation patterns in small student groups without peer leader intervention. The findings of this study revealed that students were mostly engaged in co-constructed arguments, that a discrepancy in the participation of the group members existed, and students were able to correct most of the incorrect claims on their own via argumentation. The second study, Exploration of peer leader verbal behaviors as they intervene with small groups in college general chemistry, examines the interactive discourse of the peer leaders and the students during peer leader intervention. The relationship between the verbal behaviors of the peer leaders and the student argumentation is explored in this study. The findings of this study demonstrated that peer leaders used an array of verbal behaviors to guide students to construct chemistry concepts, and that a relationship existed between student argument components and peer leader verbal behaviors. The third study, Use of Tolumin's Argumentation Scheme for student discourse to gain insight about guided inquiry activities in college chemistry , is focused on investigating the relationship between student arguments without peer leader intervention and the structure of published guided inquiry ChemActivities. The relationship between argumentation and the structure of the activities is explored with respect to prompts, questions, and the segmented Learning Cycle structure of the ChemActivities. Findings of this study revealed that prompts were effective in eliciting arguments, that convergent questions produced more arguments than directed questions, and that the structure of the Learning Cycle successfully scaffolded arguments. A semester of video data from two different small student groups facilitated by two different peer leaders was used for these three related studies. An analytic framework based on Toulmin's argumentation scheme was used for the argumentation analysis of the studies. This dissertation work focused on the three central elements of the peer-led classroom, students, peer leader, and the ChemActivities, illuminates effective discourse important for group learning. Overall, this dissertation work contributes to science education by providing both an analytic framework useful for investigating group processes and crucial strategies for conducting effective cooperative learning and promoting student argumentation. The findings of this dissertation work have valuable implications in the professional development of teachers specifically for group interventions in the implementation of cooperative learning reforms.

Quantitative Structure-Activity Relationships for Organophosphate Enzyme Inhibition (Briefing Charts)

DTIC Science & Technology

2011-09-22

OPs) are a group of pesticides that inhibit enzymes such as acetylcholinesterase. Numerous OP structural variants exist and toxicity data can be...and human toxicity studies especially for OPs lacking experimental data. 15. SUBJECT TERMS QSAR Organophosphates...structure and mechanism of toxicity c) Linking QSAR and OP PBPK/PD 2. Methods a) Physiochemical Descriptors b) Regression Techniques 3. Results a

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.

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.

Upper extremity function in stroke subjects: relationships between the international classification of functioning, disability, and health domains.

PubMed

Faria-Fortini, Iza; Michaelsen, Stella Maris; Cassiano, Janine Gomes; Teixeira-Salmela, Luci Fuscaldi

2011-01-01

Upper limb (UL) impairments are the most common disabling deficits after stroke and have complex relationships with activity and participation domains. However, relatively few studies have applied the ICF model to identify the contributions of specific UL impairments, such as muscular weakness, pain, and sensory loss, as predictors of activity and participation. The purposes of this predictive study were to evaluate the relationships between UL variables related to body functions/structures, activity, and participation domains and to determine which would best explain activity and participation with 55 subjects with chronic stroke. Body functions/structures were assessed by measures of grip, pinch, and UL strength, finger tactile sensations, shoulder pain, and cognition (MMSE); activity domain by measures of observed performance (BBT, NHPT, and TEMPA); and participation by measures of quality of life (SSQOL). Upper-limb and grip strength were related to all activity measures (0.52

Heterocyclic Schiff bases as non toxic antioxidants: Solvent effect, structure activity relationship and mechanism of action

NASA Astrophysics Data System (ADS)

Shanty, Angamaly Antony; Mohanan, Puzhavoorparambil Velayudhan

2018-03-01

Phenolic heterocyclic imine based Schiff bases from Thiophene-2-carboxaldehyde and Pyrrole-2-carboxaldehyde were synthesized and characterized as novel antioxidants. The solvent effects of these Schiff bases were determined and compared with standard antioxidants, BHA employing DPPH assay and ABTS assay. Fixed reaction time and Steady state measurement were used for study. IC50 and EC50 were calculated. Structure-activity relationship revealed that the electron donating group in the phenolic ring increases the activity where as the electron withdrawing moiety decreases the activity. The Schiff base derivatives showed antioxidant property by two different pathways namely SPLET and HAT mechanisms in DPPH assay. While in ABTS method, the reaction between ABTS radical and Schiff bases involves electron transfer followed by proton transfer (ET-PT) mechanism. The cytotoxicity of these compounds has been evaluated by MTT assay. The results showed that all these compounds are non toxic in nature.

Design synthesis and structure-activity relationship of 5-substituted (tetrahydronaphthalen-2yl)methyl with N-phenyl-N-(piperidin-2-yl)propionamide derivatives as opioid ligands.

PubMed

Deekonda, Srinivas; Rankin, David; Davis, Peg; Lai, Josephine; Vanderah, Todd W; Porecca, Frank; Hruby, Victor J

2016-01-15

Here, we report the design, synthesis and structure activity relationship of novel small molecule opioid ligands based on 5-amino substituted (tetrahydronaphthalen-2-yl)methyl moiety with N-phenyl-N-(piperidin-2-yl)propionamide derivatives. We synthesized various molecules including amino, amide and hydroxy substitution on the 5th position of the (tetrahydronaphthalen-2-yl)methyl moiety. In our further designs we replaced the (tetrahydronaphthalen-2-yl)methyl moiety with benzyl and phenethyl moiety. These N-phenyl-N-(piperidin-2-yl)propionamide analogues showed moderate to good binding affinities (850-4 nM) and were selective towards the μ opioid receptor over the δ opioid receptors. From the structure activity relationship studies, we found that a hydroxyl substitution at the 5th position of (tetrahydronapthalen-2yl)methyl group, ligands 19 and 20, showed excellent binding affinities 4 and 5 nM, respectively, and 1000 fold selectivity towards the μ opioid relative to the delta opioid receptor. The ligand 19 showed potent agonist activities 75±21 nM, and 190±42 nM in the GPI and MVD assays. Surprisingly the fluoro analogue 20 showed good agonist activities in MVD assays 170±42 nM, in contrast to its binding affinity results. Copyright © 2015 Elsevier Ltd. All rights reserved.

Synthesis and Structure-Activity Relationships of N-Dihydrocoptisine-8-ylidene Aromatic Amines and N-Dihydrocoptisine-8-ylidene Aliphatic Amides as Antiulcerative Colitis Agents Targeting XBP1.

PubMed

Xie, Meng; Zhang, Hai-Jing; Deng, An-Jun; Wu, Lian-Qiu; Zhang, Zhi-Hui; Li, Zhi-Hong; Wang, Wen-Jie; Qin, Hai-Lin

2016-04-22

In this study, natural quaternary coptisine was used as a lead compound to design and synthesize structurally stable and actively potent coptisine analogues. Of the synthesized library, 13 N-dihydrocoptisine-8-ylidene amines/amides were found not only to be noncytotoxic toward intestinal epithelial cells (IECs), but they were also able to activate the transcription of X-box-binding protein 1 (XBP1) targets to varying extents in vitro. Antiulcerative colitis (UC) activity levels were assessed at the in vitro molecular level as well as in vivo in animals using multiple biomarkers as indices. In an in vitro XBP1 transcriptional activity assay, four compounds demonstrated good dose-effect relationships with EC50 values of 0.0708-0.0132 μM. Moreover, two compounds were confirmed to be more potent in vivo than a positive control, demonstrating a curative effect for UC in experimental animals. Thus, the findings of this study suggest that these coptisine analogues are promising candidates for the development of anti-UC drugs.

The Structure-Activity Relationship of the 3-Oxy Site in the Anticonvulsant (R)-N-Benzyl 2-Acetamido-3-methoxypropionamide

PubMed Central

Morieux, Pierre; Salomé, Christophe; Park, Ki Duk; Stables, James P.; Kohn, Harold

2010-01-01

Lacosamide ((R)-N-benzyl 2-acetamido-3-methoxypropionamide, (R)-1) is a low molecular weight anticonvulsant recently introduced in the United States and Europe for adjuvant treatment of partial-onset seizures in adults. In this study, we define the structure-activity relationship (SAR) for the compound's 3-oxy site. Placement of small non-polar, non-bulky substituents at the 3-oxy site provided compounds with pronounced seizure protection in the maximal electroshock (MES) seizure test with activities similar to (R)-1. The anticonvulsant activity loss that accompanied introduction of larger moieties at the 3-oxy site in (R)-1 was offset, in part, by including unsaturated groups at this position. Our findings were similar to a recently reported SAR study of the 4′-benzylamide site in (R)-1 (J. Med. Chem.2010, 53, 1288–1305). Together, these results indicate that both the 3-oxy and 4′-benzylamide positions in (R)-1 can accommodate non-bulky, hydrophobic groups and still retain pronounced anticonvulsant activities in rodents in the MES seizure model. PMID:20614888

Structure-activity relationship study of peptidomimetic aldehydes as enterovirus 71 3C protease inhibitors.

PubMed

Zhai, Yangyang; Ma, Yuying; Ma, Fei; Nie, Quandeng; Ren, Xuejiao; Wang, Yaxin; Shang, Luqing; Yin, Zheng

2016-11-29

A series of peptidomimetic aldehydes were designed, synthesized, and evaluated for their biochemical activity against 3C protease (3C pro ) and anti-enterovirus 71 (EV71) activity in vitro. Molecular docking revealed that 5s (IC 50  = 0.22 ± 0.07 μM, EC 50  = 0.18 ± 0.05 μM) could bind well to the active site of EV71 3C pro , which was consistent with the biological data compared to reference 5a (IC 50  = 0.54 ± 0.02 μM, EC 50  = 0.26 ± 0.07 μM). Structure and relationship study led to the discovery of aldehyde 5x (IC 50  = 0.10 ± 0.02 μM, EC 50  = 0.11 ± 0.07 μM), which exhibited the most potent 3C pro inhibitory and antiviral activity. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Structure-activity relationships of neoechinulin A analogues with cytoprotection against peroxynitrite-induced PC12 cell death.

PubMed

Kimoto, Kuniaki; Aoki, Toshiaki; Shibata, Yasushi; Kamisuki, Shinji; Sugawara, Fumio; Kuramochi, Kouji; Nakazaki, Atsuo; Kobayashi, Susumu; Kuroiwa, Kenji; Watanabe, Nobuo; Arai, Takao

2007-10-01

Neoechinulin A, an alkaloid from Eurotium rubrum Hiji025, protected neuronal PC12 cells against cell death induced by peroxynitrite derived from SIN-1 (3-(4-morpholinyl)sydnonimine hydrochloride). In this study, we investigated the structure-activity relationships of neoechinulin A and a set of its analogues by using assays to measure anti-nitration and antioxidant activities and cytoprotection against SIN-1-induced PC12 cell death. The presence of the diketopiperazine ring was essential for both the antioxidant and anti-nitration activities of neoechinulin A derivatives. Nevertheless, a derivative lacking the diketopiperazine ring could still protect PC12 cells against SIN-1 cytotoxicity. An acyclic analogue completely lost the cytoprotective effect while retaining its antioxidant/anti-nitration activities. Pre-incubation of the cells with neoechinulin A for at least 12 hours was essential for the cells to gain SIN-1 resistance. These results suggest that neoechinulin A endows the cells with cytoprotection through a biological effect different from the apparent antioxidant/anti-nitration activities.

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.

Studies of the structure-antioxidant activity relationships and antioxidant activity mechanism of iridoid valepotriates and their degradation products

PubMed Central

Wang, Feifei; Zhang, Yumei; Wu, Shouhai; He, Yi; Dai, Zhong; Liu, Bin

2017-01-01

Oxidative stress has been associated with diverse diseases, including obesity, cancer and neurodegeneration. In fact, Valeriana jatamansi Jones (valerian) and its extracts possess strong antioxidant activities that extend their application in clinical practice to the treatment of these illnesses, even though the underlying mechanisms are not well understood. Iridoid valepotriate, a characteristic iridoid ester in valerian with poor chemical stability, possesses considerable antioxidant components. The original compounds and their degradation products have been found to exhibit strong antioxidant activities. However, the relationship between their structure and antioxidant effects and the mechanism underlying their oxidation resistance remain unclear. A forced degradation study using three iridoid valepotriates (valtrate, acevaltrate and 1-β acevaltrate) was performed in this work, and the structures of their degradation products were estimated by TLC-MS and LC-MS. Comparison of the antioxidant activities of the iridoid valepotriates before and after forced degradation revealed that degradation reduced the activities of the iridoid valepotriates in free radical scavenging and cytotoxic and cell apoptosis tests. The results suggested that the oxirane nucleus is important for defining the antioxidant profile of iridoid valepotriate. We uncovered possible mechanisms that could explain the antioxidant activities, including the generation of two hydroxyl groups through intramolecular transfer of an H• from an oxirane ring and a reduction in ROS levels through interactions with GABAergic signalling pathways. PMID:29232391

Design, evaluation and structure-activity relationship studies of the AChE reactivators against organophosphorus pesticides.

PubMed

Musilek, Kamil; Dolezal, Martin; Gunn-Moore, Frank; Kuca, Kamil

2011-07-01

Organophosphate pesticides (OPPs; e.g. chlorpyrifos, diazinon, paraoxon) are a wide and heterogeneous group of organophosphorus compounds. Their biological activity of inhibiting acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) ranks them as life endangering agents. The necessary treatment after OPP exposure involves the use of parasympatolytics (e.g. atropine), oxime reactivators (e.g. obidoxime), and anticonvulsive drugs (e.g. diazepam). Therefore, the reactivators of AChE are essential compounds in the treatment of OPP intoxications. Commercial AChE reactivators (e.g. pralidoxime, HI-6, obidoxime, trimedoxime, methoxime) were originally developed for other members of the organophosphate family, such as nerve agents (e.g. sarin, soman, tabun, VX). Pralidoxime, HI-6, and methoxime were found to be weak reactivators of OPP-inhibited AChE. Obidoxime and trimedoxime showed satisfactory reactivation against various OPPs with minor toxicity issues. During the last two decades, the treatment of OPP exposure has become more widely discussed because of growing agricultural production, industrialization, and harmful social issues (e.g. suicides). In this review is the summarized design, evaluation, and structure-activity relationship studies of recently produced AChE reactivators. Since pralidoxime, over 300 oximes have been produced or tested against OPP poisoning, and several novel compounds show very promising abilities as comparable (or higher) to commercial oximes. Some of these are highlighted for their further testing of OPP exposure and, additionally, the main structure-activity relationship of AChE reactivators against OPP is discussed. © 2009 Wiley Periodicals, Inc.

Structure-Activity Relationships of Small Molecule Autotaxin Inhibitors with a Discrete Binding Mode.

PubMed

Miller, Lisa M; Keune, Willem-Jan; Castagna, Diana; Young, Louise C; Duffy, Emma L; Potjewyd, Frances; Salgado-Polo, Fernando; Engel García, Paloma; Semaan, Dima; Pritchard, John M; Perrakis, Anastassis; Macdonald, Simon J F; Jamieson, Craig; Watson, Allan J B

2017-01-26

Autotaxin (ATX) is a secreted enzyme responsible for the hydrolysis of lysophosphatidylcholine (LPC) to the bioactive lysophosphatidic acid (LPA) and choline. The ATX-LPA signaling pathway is implicated in cell survival, migration, and proliferation; thus, the inhibition of ATX is a recognized therapeutic target for a number of diseases including fibrotic diseases, cancer, and inflammation, among others. Many of the developed synthetic inhibitors for ATX have resembled the lipid chemotype of the native ligand; however, a small number of inhibitors have been described that deviate from this common scaffold. Herein, we report the structure-activity relationships (SAR) of a previously reported small molecule ATX inhibitor. We show through enzyme kinetics studies that analogues of this chemotype are noncompetitive inhibitors, and by using a crystal structure with ATX we confirm the discrete binding mode.

Insect prophenoloxidase: the view beyond immunity

PubMed Central

Lu, Anrui; Zhang, Qiaoli; Zhang, Jie; Yang, Bing; Wu, Kai; Xie, Wei; Luan, Yun-Xia; Ling, Erjun

2014-01-01

Insect prophenoloxidase (PPO) is an important innate immunity protein due to its involvement in cellular and humoral defense. It belongs to a group of type-3 copper-containing proteins that occurs in almost all organisms. Insect PPO has been studied for over a century, and the PPO activation cascade is becoming clearer. The insect PPO activation pathway incorporates several important proteins, including pattern-recognition receptors (PGRP, β GRP, and C-type lectins), serine proteases, and serine protease inhibitors (serpins). Due to their complexity, PPO activation mechanisms vary among insect species. Activated phenoloxidase (PO) oxidizes phenolic molecules to produce melanin around invading pathogens and wounds. The crystal structure of Manduca sexta PPO shows that a conserved amino acid, phenylalanine (F), can block the active site pocket. During activation, this blocker must be dislodged or even cleaved at the N-terminal sequence to expose the active site pockets and allow substrates to enter. Thanks to the crystal structure of M. sexta PPO, some domains and specific amino acids that affect PPO activities have been identified. Further studies of the relationship between PPO structure and enzyme activities will provide an opportunity to examine other type-3 copper proteins, and trace when and why their various physiological functions evolved. Recent researches show that insect PPO has a relationship with neuron activity, longevity, feces melanization (phytophagous insects) and development, which suggests that it is time for us to look back on insect PPO beyond the view of immunity in this review. PMID:25071597

In Vitro Phytotoxicity and Antioxidant Activity of Selected Flavonoids

PubMed Central

De Martino, Laura; Mencherini, Teresa; Mancini, Emilia; Aquino, Rita Patrizia; De Almeida, Luiz Fernando Rolim; De Feo, Vincenzo

2012-01-01

The knowledge of flavonoids involved in plant-plant interactions and their mechanisms of action are poor and, moreover, the structural characteristics required for these biological activities are scarcely known. The objective of this work was to study the possible in vitro phytotoxic effects of 27 flavonoids on the germination and early radical growth of Raphanus sativus L. and Lepidium sativum L., with the aim to evaluate the possible structure/activity relationship. Moreover, the antioxidant activity of the same compounds was also evaluated. Generally, in response to various tested flavonoids, germination was only slightly affected, whereas significant differences were observed in the activity of the various tested flavonoids against radical elongation. DPPH test confirms the antioxidant activity of luteolin, quercetin, catechol, morin, and catechin. The biological activity recorded is discussed in relation to the structure of compounds and their capability to interact with cell structures and physiology. No correlation was found between phytotoxic and antioxidant activities. PMID:22754304

Distributed Structure Searchable Toxicity

EPA Pesticide Factsheets

The Distributed Structure Searchable Toxicity (DSSTox) online resource provides high quality chemical structures and annotations in association with toxicity data. It helps to build a data foundation for improved structure-activity relationships and predictive toxicology. DSSTox publishes summarized chemical activity representations for structure-activity modeling and provides a structure browser. This tool also houses the chemical inventories for the ToxCast and Tox21 projects.

Modifications of the chemical structure of phenolics differentially affect physiological activities in pulvinar cells of Mimosa pudica L. I. Multimode effect on early membrane events.

PubMed

Rocher, Françoise; Dédaldéchamp, Fabienne; Saeedi, Saed; Fleurat-Lessard, Pierrette; Chollet, Jean-Francois; Roblin, Gabriel

2014-11-01

A study of the structure-activity relationship carried out on several benzoic acid-related phenolics indicates that this type of compounds hinders the osmocontractile reaction of pulvinar cells in the range of 0-100%. Tentatively, we tried to find a way that could explain this differential action. With this aim, the relationship between the inhibitory effect and important molecular physico-chemical parameters (namely lipophilicity and degree of dissociation) was drawn. In addition, the effect of a variety of these compounds was investigated on their capacity to modify the electrical transmembrane potential and induce modifications in proton fluxes. Finally, using plasma membrane vesicles purified from pulvinar tissues, we examined the effects of some selected compounds on the proton pump activity and catalytic activity of the plasma membrane H(+)-ATPase. Taken together, the results indicate that a modification of the molecular structure of phenolics may induce important variation in the activity of the compound on these early membrane events. Among the tested phenolics, salicylic acid (SA) and acetylsalicylic acid (ASA, aspirin) are of particuler note, as they showed atypical effects on the physiological processes studied. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Synthesis and biological activities of turkesterone 11α-acyl derivatives

PubMed Central

Dinan, Laurence; Bourne, Pauline; Whiting, Pensri; Tsitsekli, Ada; Saatov, Ziyadilla; Dhadialla, Tarlochan S.; Hormann, Robert E.; Lafont, René; Coll, Josep

2003-01-01

Turkesterone is a phytoecdysteroid possessing an 11α-hydroxyl group. It is an analogue of the insect steroid hormone 20-hydroxyecdysone. Previous ecdysteroid QSAR and molecular modelling studies predicted that the cavity of the ligand binding domain of the ecdysteroid receptor would possess space in the vicinity of C-11/C-12 of the ecdysteroid. We report the regioselective synthesis of a series of turkesterone 11α-acyl derivatives in order to explore this possibility. The structures of the analogues have been unambiguously determined by spectroscopic means (NMR and low-resolution mass spectrometry). Purity was verified by HPLC. Biological activities have been determined in Drosophila melanogaster BII cell-based bioassay for ecdysteroid agonists and in an in vitro radioligand-displacement assay using bacterially-expressed D. melanogaster EcR/USP receptor proteins. The 11α-acyl derivatives do retain a significant amount of biological activity relative to the parent ecdysteroid. Further, although activity initially drops with the extension of the acyl chain length (C2 to C4), it then increases (C6 to C10), before decreasing again (C14 and C20). The implications of these findings for the interaction of ecdysteroids with the ecdysteroid receptor and potential applications in the generation of affinity-labelled and fluorescently-tagged ecdysteroids are discussed. Abbreviation: CoMFA comparative molecular field analysis DCM dichloromethane DMF dimethylformamide DMP 2,2-dimethoxypropane 4D-QSAR 4-dimensional quantitative structure-activity relationship EcR ecdysteroid receptor EcRE ecdysteroid response element HPLC high-performance liquid chromatography LBD ligand-binding domain NMR nuclear magnetic resonance ponA ponasterone A QSAR quantitative structure-activity relationship RXR retinoid X receptor SAR structure-activity relationship SPE solid-phase extraction THF tetrahydrofuran TLC thin-layer chromatography p-TsOH para-toluenesulphonic acid USP ultraspiracle UV-VIS ultraviolet-visible PMID:15841223

Dietary protection against free radicals: a case for multiple testing to establish structure-activity relationships for antioxidant potential of anthocyanic plant species.

PubMed

Philpott, Martin; Lim, Chiara Cheng; Ferguson, Lynnette R

2009-03-01

DNA damage by reactive species is associated with susceptibility to chronic human degenerative disorders. Anthocyanins are naturally occurring antioxidants, that may prevent or reverse such damage. There is considerable interest in anthocyanic food plants as good dietary sources, with the potential for reducing susceptibility to chronic disease. While structure-activity relationships have provided guidelines on molecular structure in relation to free hydroxyl-radical scavenging, this may not cover the situation in food plants where the anthocyanins are part of a complex mixture, and may be part of complex structures, including anthocyanic vacuolar inclusions (AVIs). Additionally, new analytical methods have revealed new structures in previously-studied materials. We have compared the antioxidant activities of extracts from six anthocyanin-rich edible plants (red cabbage, red lettuce, blueberries, pansies, purple sweetpotato skin, purple sweetpotato flesh and Maori potato flesh) using three chemical assays (DPPH, TRAP and ORAC), and the in vitro Comet assay. Extracts from the flowering plant, lisianthus, were used for comparison. The extracts showed differential effects in the chemical assays, suggesting that closely related structures have different affinities to scavenge different reactive species. Integration of anthocyanins to an AVI led to more sustained radical scavenging activity as compared with the free anthocyanin. All but the red lettuce extract could reduce endogenous DNA damage in HT-29 colon cancer cells. However, while extracts from purple sweetpotato skin and flesh, Maori potato and pansies, protected cells against subsequent challenge by hydrogen peroxide at 0 degrees C, red cabbage extracts were pro-oxidant, while other extracts had no effect. When the peroxide challenge was at 37 degrees C, all of the extracts appeared pro-oxidant. Maori potato extract, consistently the weakest antioxidant in all the chemical assays, was more effective in the Comet assays. These results highlight the dangers of generalising to potential health benefits, based solely on identification of high anthocyanic content in plants, results of a single antioxidant assay and traditional approaches to structure activity relationships. Subsequent studies might usefully consider complex mixtures and a battery of assays.

8-Amido-Bearing pseudomycin B (PSB) analogue: novel antifungal agents.

PubMed

Zhang, Y Z; Sun, X; Zeckner, D J; Sachs, R K; Current, W L; Chen, S H

2001-01-22

During the course of a structure-activity relationship (SAR) study on novel depsinonapeptide pseudomycin B, we synthesized a total of 12 8-amidopseudomycin analogues via standard two-step sequence from either ZPSB 2 or AllocPSB 3. A number of these amides exhibited good in vitro antifungal activities.

Contemporary Student Activism: The Educational Contexts of Socially-Responsible Civic Engagement

ERIC Educational Resources Information Center

Barnhardt, Cassie L.

2012-01-01

Contemporary higher education leaders tend to view campus based activism as an outgrowth of an educational experience that inspires and leads students to engage in civic action for the purpose of alleviating systemic social, economic, or political injustices. Accordingly, this study explores the relationships between the structural characteristics…

Advances on Semisynthesis, Total Synthesis, and Structure-Activity Relationships of Honokiol and Magnolol Derivatives.

PubMed

Yang, Chun; Zhi, Xiaoyan; Xu, Hui

2016-01-01

Honokiol and magnolol (an isomer of honokiol) are small-molecule polyphenols isolated from the barks of Magnolia officinalis, which have been widely used in traditional Chinese and Japanese medicines. In the last decade, a variety of biological properties of honokiol and magnolol (e.g., anti-oxidativity, antitumor activity, anti-depressant activity, anti-inflammatory activity, neuroprotective activity, anti-diabetic activity, antiviral activity, and antimicrobial activity) have been reported. Meanwhile, certain mechanisms of action of some biological activities were also investigated. Moreover, many analogs of honokiol and magnolol were prepared by structural modification or total synthesis, and some exhibited very potent pharmacological activities with improved water solubility. Therefore, the present review will provide a systematic coverage on recent developments of honokiol and magnolol derivatives in regard to semisynthesis, total synthesis, and structure-activity relationships from 2000 up to now.

Structural and Immunological Activity Characterization of a Polysaccharide Isolated from Meretrix meretrix Linnaeus

PubMed Central

Li, Li; Li, Heng; Qian, Jianying; He, Yongfeng; Zheng, Jialin; Lu, Zhenming; Xu, Zhenghong; Shi, Jinsong

2015-01-01

Polysaccharides from marine clams perform various biological activities, whereas information on structure is scarce. Here, a water-soluble polysaccharide MMPX-B2 was isolated from Meretrix meretrix Linnaeus. The proposed structure was deduced through characterization and its immunological activity was investigated. MMPX-B2 consisted of d-glucose and d-galctose residues at a molar ratio of 3.51:1.00. The average molecular weight of MMPX-B2 was 510 kDa. This polysaccharide possessed a main chain of (1→4)-linked-α-d-glucopyranosyl residues, partially substituted at the C-6 position by a few terminal β-d-galactose residues or branched chains consisting of (1→3)-linked β-d-galactose residues. Preliminary immunological tests in vitro showed that MMPX-B2 could stimulate the murine macrophages to release various cytokines, and the structure-activity relationship was then established. The present study demonstrated the potential immunological activity of MMPX-B2, and provided references for studying the active ingredients in M. meretrix. PMID:26729136

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.

40 CFR 132.2 - Definitions.

Code of Federal Regulations, 2012 CFR

2012-07-01

... Species Act. Existing Great Lakes discharger is any building, structure, facility, or installation from... discharger is any building, structure, facility, or installation from which there is or may be a “discharge... monitoring of the contaminant. Quantitative structure activity relationship (QSAR) or structure activity...

Structure—activity relationships for insecticidal carbamates*

PubMed Central

Metcalf, Robert L.

1971-01-01

Carbamate insecticides are biologically active because of their structural complementarity to the active site of acetylcholinesterase (AChE) and their consequent action as substrates with very low turnover numbers. Carbamates behave as synthetic neurohormones that produce their toxic action by interrupting the normal action of AChE so that acetylcholine accumulates at synaptic junctions. The necessary properties for a suitable insecticidal carbamate are lipid solubility, suitable structural complementarity to AChE, and sufficient stability to multifunction-oxidase detoxification. The relationships between the structure and the activity of a large number of synthetic carbamates are analysed in detail, with particular attention to the second of these properties. PMID:5315358

Isolation of Insecticidal Constituent from Ruta graveolens and Structure-Activity Relationship Studies against Stored-Food Pests (Coleoptera).

PubMed

Jeon, Ju-Hyun; Lee, Sang-Guei; Lee, Hoi-Seon

2015-08-01

Isolates from essential oil extracted from the flowers and leaves of Ruta graveolens and commercial phenolic analogs were evaluated using fumigant and contact toxicity bioassays against adults of the stored-food pests Sitophilus zeamais, Sitophilus oryzae, and Lasioderma serricorne. The insecticidal activity of these compounds was then compared with that of the synthetic insecticide dichlorvos. To investigate the structure-activity relationships, the activity of 2-isopropyl-5-methylphenol and its analogs was examined against these stored-food pests. Based on the 50% lethal dose, the most toxic compound against S. zeamais was 3-isopropylephenol, followed by 2-isopropylphenol, 4-isopropylphenol, 5-isopropyl-2-methylphenol, 2-isopropyl-5-methylphenol, 3-methylphenol, and 2-methylphenol. Similar results were observed with phenolic compounds against S. oryzae. However, when 2-isopropyl-5-methylphenol isolated from R. graveolens oil and its structurally related analogs were used against L. serricorne, little or no insecticidal activity was found regardless of bioassay. These results indicate that introducing and changing the positions of functional groups in the phenol skeleton have an important effect on insecticidal activity of these compounds against stored-food pests.

Synthesis and Structure activity relationships of EGCG Analogues, A Recently Identified Hsp90 Inhibitor

PubMed Central

Khandelwal, Anuj; Hall, Jessica

2014-01-01

Epigallocatechin-3-gallate (EGCG), the principal polyphenol isolated from green tea, was recently shown to inhibit Hsp90, however structure-activity relationships for this natural product have not yet been produced. Herein, we report the synthesis and biological evaluation of EGCG analogues to establish structure-activity relationships between EGCG and Hsp90. All four rings as well as the linker connecting the C- and the D-rings were systematically investigated, which led to the discovery of compounds that inhibit Hs90 and display improvement in efficacy over EGCG. Anti-proliferative activity of all the analogues was determined against MCF-7 and SKBr3 cell lines and Hsp90 inhibitory activity of four most potent analogues was further evaluated by western blot analyses and degradation of Hsp90-dependent client proteins. Prenyl substituted aryl ester of 3,5-dihydroxychroman-3-ol ring system was identified as novel scaffold that exhibit Hsp90 inhibitory activity. PMID:23834230

The anti-inflammatory activity of dillapiole and some semisynthetic analogues.

PubMed

Parise-Filho, Roberto; Pastrello, Michelli; Pereira Camerlingo, Carla Emygdio; Silva, Gisele Juni; Agostinho, Leonardo Aguiar; de Souza, Thaís; Motter Magri, Fátima Maria; Ribeiro, Roberto Rodrigues; Brandt, Carlos Alberto; Polli, Michelle Carneiro

2011-11-01

Piper aduncum L. (Piperaceae) produces an essential oil (dillapiole) with great exploitative potential and it has proven effects against traditional cultures of phytopathogens, such as fungi, bacteria and mollusks, as well as analgesic action with low levels of toxicity. This study investigated the in vivo anti-inflammatory activity of dillapiole. Furthermore, in order to elucidate its structure-anti-inflammatory activity relationship (SAR), semisynthetic analogues were proposed by using the molecular simplification strategy. Dillapiole and safrole were isolated and purified using column chromatography. The semisynthetic analogues were obtained by using simple organic reactions, such as catalytic reduction and isomerization. All the analogues were purified by column chromatography and characterized by (1)H and (13)C NMR. The anti-inflammatory activities of dillapiole and its analogues were studied in carrageenan-induced rat paw edema model. Dillapiole and di-hydrodillapiole significantly (p<0.05) inhibited rat paw edema. All the other substances tested, including safrole, were less powerful inhibitors with activities inferior to that of indomethacin. These findings showed that dillapiole and di-hydrodillapiole have moderate anti-phlogistic properties, indicating that they can be used as prototypes for newer anti-inflammatory compounds. Structure-activity relationship studies revealed that the benzodioxole ring is important for biological activity as well as the alkyl groups in the side chain and the methoxy groups in the aromatic ring.

Novel amide-based inhibitors of inosine 5'-monophosphate dehydrogenase.

PubMed

Watterson, Scott H; Liu, Chunjian; Dhar, T G Murali; Gu, Henry H; Pitts, William J; Barrish, Joel C; Fleener, Catherine A; Rouleau, Katherine; Sherbina, N Z; Hollenbaugh, Diane L; Iwanowicz, Edwin J

2002-10-21

A series of novel amide-based small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH) was explored. The synthesis and the structure-activity relationships (SARs) derived from in vitro studies are described.

Rapid synthesis of triazine inhibitors of inosine monophosphate dehydrogenase.

PubMed

Pitts, William J; Guo, Junqing; Dhar, T G Murali; Shen, Zhongqi; Gu, Henry H; Watterson, Scott H; Bednarz, Mark S; Chen, Bang Chi; Barrish, Joel C; Bassolino, Donna; Cheney, Daniel; Fleener, Catherine A; Rouleau, Katherine A; Hollenbaugh, Diane L; Iwanowicz, Edwin J

2002-08-19

A series of novel triazine-based small molecule inhibitors (IV) of inosine monophosphate dehydrogenase was prepared. The synthesis and the structure-activity relationships (SAR) derived from in vitro studies are described.

Psychometric properties of the Interpersonal Relationship Inventory-Short Form for active duty female service members.

PubMed

Nayback-Beebe, Ann M; Yoder, Linda H

2011-06-01

The Interpersonal Relationship Inventory-Short Form (IPRI-SF) has demonstrated psychometric consistency across several demographic and clinical populations; however, it has not been psychometrically tested in a military population. The purpose of this study was to psychometrically evaluate the reliability and component structure of the IPRI-SF in active duty United States Army female service members (FSMs). The reliability estimates were .93 for the social support subscale and .91 for the conflict subscale. Principal component analysis demonstrated an obliquely rotated three-component solution that accounted for 58.9% of the variance. The results of this study support the reliability and validity of the IPRI-SF for use in FSMs; however, a three-factor structure emerged in this sample of FSMs post-deployment that represents "cultural context." Copyright © 2011 Wiley Periodicals, Inc.

Exploring the anti-cancer activity of novel thiosemicarbazones generated through the combination of retro-fragments: dissection of critical structure-activity relationships.

PubMed

Serda, Maciej; Kalinowski, Danuta S; Rasko, Nathalie; Potůčková, Eliška; Mrozek-Wilczkiewicz, Anna; Musiol, Robert; Małecki, Jan G; Sajewicz, Mieczysław; Ratuszna, Alicja; Muchowicz, Angelika; Gołąb, Jakub; Simůnek, Tomáš; Richardson, Des R; Polanski, Jaroslaw

2014-01-01

Thiosemicarbazones (TSCs) are an interesting class of ligands that show a diverse range of biological activity, including anti-fungal, anti-viral and anti-cancer effects. Our previous studies have demonstrated the potent in vivo anti-tumor activity of novel TSCs and their ability to overcome resistance to clinically used chemotherapeutics. In the current study, 35 novel TSCs of 6 different classes were designed using a combination of retro-fragments that appear in other TSCs. Additionally, di-substitution at the terminal N4 atom, which was previously identified to be critical for potent anti-cancer activity, was preserved through the incorporation of an N4-based piperazine or morpholine ring. The anti-proliferative activity of the novel TSCs were examined in a variety of cancer and normal cell-types. In particular, compounds 1d and 3c demonstrated the greatest promise as anti-cancer agents with potent and selective anti-proliferative activity. Structure-activity relationship studies revealed that the chelators that utilized "soft" donor atoms, such as nitrogen and sulfur, resulted in potent anti-cancer activity. Indeed, the N,N,S donor atom set was crucial for the formation of redox active iron complexes that were able to mediate the oxidation of ascorbate. This further highlights the important role of reactive oxygen species generation in mediating potent anti-cancer activity. Significantly, this study identified the potent and selective anti-cancer activity of 1d and 3c that warrants further examination.

Structure-anti-MRSA activity relationship of macrocyclic bis(bibenzyl) derivatives.

PubMed

Sawada, Hiromi; Onoda, Kenji; Morita, Daichi; Ishitsubo, Erika; Matsuno, Kenji; Tokiwa, Hiroaki; Kuroda, Teruo; Miyachi, Hiroyuki

2013-12-15

We synthesized a series of macrocyclic bis(bibenzyl) derivatives, including riccardin-, isoplagiochin- and marchantin-class structures, and evaluated their antibacterial activity towards methicillin-resistant Staphylococcus aureus (anti-MRSA activity). The structure-activity relationships and the results of molecular dynamics simulations indicated that bis(bibenzyl)s with potent anti-MRSA activity commonly have a 4-hydroxyl group at the D-benzene ring and a 2-hydroxyl group at the C-benzene ring in the hydrophilic part of the molecule, and an unsubstituted phenoxyphenyl group in the hydrophobic part of the molecule containing the A-B-benzene rings. Pharmacological characterization of the bis(bibenzyl) derivatives and 2-phenoxyphenol fragment 25, previously proposed as the minimum structure of riccardin C 1 for anti-MRSA activity, indicated that they have different action mechanisms: the bis(bibenzyl)s are bactericidal, while 25 is bacteriostatic, showing only weak bactericidal activity. Copyright © 2013 Elsevier Ltd. All rights reserved.

TOWARDS REFINED USE OF TOXICITY DATA IN ...

EPA Pesticide Factsheets

In 2003, an International Life Sciences Institute (ILSI) Working Group examined the potential of statistically based structure-activity relationship (SAR) models for use in screening environmental contaminants for possible developmental toxicants. In 2003, an International Life Sciences Institute (ILSI) Working Group examined the potential of statistically based structure-activity relationship (SAR) models for use in screening environmental contaminants for possible developmental toxicants.

Synthesis, biological evaluation, and 3D QSAR study of 2-methyl-4-oxo-3-oxetanylcarbamic acid esters as N-acylethanolamine acid amidase (NAAA) inhibitors.

PubMed

Ponzano, Stefano; Berteotti, Anna; Petracca, Rita; Vitale, Romina; Mengatto, Luisa; Bandiera, Tiziano; Cavalli, Andrea; Piomelli, Daniele; Bertozzi, Fabio; Bottegoni, Giovanni

2014-12-11

N-(2-Oxo-3-oxetanyl)carbamic acid esters have recently been reported to be noncompetitive inhibitors of the N-acylethanolamine acid amidase (NAAA) potentially useful for the treatment of pain and inflammation. In the present study, we further explored the structure-activity relationships of the carbamic acid ester side chain of 2-methyl-4-oxo-3-oxetanylcarbamic acid ester derivatives. Additional favorable features in the design of potent NAAA inhibitors have been found together with the identification of a single digit nanomolar inhibitor. In addition, we devised a 3D QSAR using the atomic property field method. The model turned out to be able to account for the structural variability and was prospectively validated by designing, synthesizing, and testing novel inhibitors. The fairly good agreement between predictions and experimental potency values points to this 3D QSAR model as the first example of quantitative structure-activity relationships in the field of NAAA inhibitors.

Discovery of novel DAPY-IAS hybrid derivatives as potential HIV-1 inhibitors using molecular hybridization based on crystallographic overlays.

PubMed

Huang, Boshi; Wang, Xueshun; Liu, Xinhao; Chen, Zihui; Li, Wanzhuo; Sun, Songkai; Liu, Huiqing; Daelemans, Dirk; De Clercq, Erik; Pannecouque, Christophe; Zhan, Peng; Liu, Xinyong

2017-08-15

Crystallographic overlap studies and pharmacophoric analysis indicated that diarylpyrimidine (DAPY)-based HIV-1 NNRTIs showed a similar binding mode and pharmacophoric features as indolylarylsulfones (IASs), another class of potent NNRTIs. Thus, a novel series of DAPY-IAS hybrid derivatives were identified as newer NNRTIs using structure-based molecular hybridization. Some target compounds exhibited moderate activities against HIV-1 IIIB strain, among which the two most potent inhibitors possessed EC 50 values of 1.48μM and 1.61μM, respectively. They were much potent than the reference drug ddI (EC 50 =76.0μM) and comparable to 3TC (EC 50 =2.54μM). Compound 7a also exhibited the favorable selectivity index (SI=80). Preliminary structure-activity relationships (SARs), structure-cytotoxicity relationships, molecular modeling studies, and in silico calculation of physicochemical properties of these new inhibitors were also discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Novel 5-aryl-1,3-dihydro-indole-2-thiones. potent, orally active progesterone receptor agonists.

PubMed

Fensome, Andrew; Koko, Marci; Wrobel, Jay; Zhang, Puwen; Zhang, Zhiming; Cohen, Jeffrey; Lundeen, Scott; Rudnick, Kelly; Zhu, Yuan; Winneker, Richard

2003-04-07

During the course of our studies on 3,3-disubstituted-5-aryloxindoles derived progesterone receptor (PR) antagonists we discovered that changing the amide funtionality to a thio-amide resulted in compounds displaying potent PR agonist activity. In this communication, the synthesis, structure activity relationships (SAR) and in vivo activity of various 5-arylthio-oxindoles will be discussed.

Structure-Activity Relationships for in vitro Diuretic Activity of CAP2b in the Housefly

DTIC Science & Technology

2007-01-01

p e p t i d e s 2 8 ( 2 0 0 7 ) 5 7 – 6 1Structure-activity relationships for in vitro diuretic activity of CAP2b in the housefly Ronald J. Nachman a...the peptide Manse-CAP2b (pELYAFPRV-NH2) were assayed for diuretic activity on Malpighian tubules of the housefly Musca domestica (M. domestica). The C...required the C-terminal heptapeptide, which was equipotent with the most active of the native housefly CAP2b peptides. Replacement of Arg7 and Val8 with

An Empirical Study of Students' Understanding of a Logical Structure in the Definition of Limit via the epsilon-Strip Activity

ERIC Educational Resources Information Center

Roh, Kyeong Hah

2010-01-01

This study explored students' understanding of a logical structure in defining the limit of a sequence, focusing on the relationship between epsilon and N. The subjects of this study were college students who had already encountered the concept of limit but did not have any experience with rigorous proofs using the epsilon-N definition. This study…

Antimalarial agents against both sexual and asexual parasites stages: structure-activity relationships and biological studies of the Malaria Box compound 1-[5-(4-bromo-2-chlorophenyl)furan-2-yl]-N-[(piperidin-4-yl)methyl]methanamine (MMV019918) and analogues.

PubMed

Vallone, Alessandra; D'Alessandro, Sarah; Brogi, Simone; Brindisi, Margherita; Chemi, Giulia; Alfano, Gloria; Lamponi, Stefania; Lee, Soon Goo; Jez, Joseph M; Koolen, Karin J M; Dechering, Koen J; Saponara, Simona; Fusi, Fabio; Gorelli, Beatrice; Taramelli, Donatella; Parapini, Silvia; Caldelari, Reto; Campiani, Giuseppe; Gemma, Sandra; Butini, Stefania

2018-04-25

Therapies addressing multiple stages of Plasmodium falciparum life cycle are highly desirable for implementing malaria elimination strategies. MMV019918 (1, 1-[5-(4-bromo-2-chlorophenyl)furan-2-yl]-N-[(piperidin-4-yl)methyl]methanamine) was selected from the MMV Malaria Box for its dual activity against both asexual stages and gametocytes. In-depth structure-activity relationship studies and cytotoxicity evaluation led to the selection of 25 for further biological investigation. The potential transmission blocking activity of 25 versus P. falciparum was confirmed through the standard membrane-feeding assay. Both 1 and 25 significantly prolonged atrioventricular conduction time in Langendorff-isolated rat hearts, and showed inhibitory activity of Ba 2+ current through Ca v 1.2 channels. An in silico target-fishing study suggested the enzyme phosphoethanolamine methyltransferase (PfPMT) as a potential target. However, compound activity against PfPMT did not track with the antiplasmodial activity, suggesting the latter activity relies on a different molecular target. Nevertheless, 25 showed interesting activity against PfPMT, which could be an important starting point for the identification of more potent inhibitors active against both sexual and asexual stages of the parasite. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Do Perceptions of Competence Mediate The Relationship Between Fundamental Motor Skill Proficiency and Physical Activity Levels of Children in Kindergarten?

PubMed

Crane, Jeff R; Naylor, Patti J; Cook, Ryan; Temple, Viviene A

2015-07-01

Perceptions of competence mediate the relationship between motor skill proficiency and physical activity among older children and adolescents. This study examined kindergarten children's perceptions of physical competence as a mediator of the relationship between motor skill proficiency as a predictor variable and physical activity levels as the outcome variable; and also with physical activity as a predictor and motor skill proficiency as the outcome. Participants were 116 children (mean age = 5 years 7 months, 58% boys) from 10 schools. Motor skills were measured using the Test of Gross Motor Development-2 and physical activity was monitored through accelerometry. Perceptions of physical competence were measured using The Pictorial Scale of Perceived Competence and Social Acceptance for Young Children, and the relationships between these variables were examined using a model of mediation. The direct path between object control skills and moderate-vigorous physical activity (MVPA) was significant and object control skills predicted perceived physical competence. However, perceived competence did not mediate the relationship between object control skills and MVPA. The significant relationship between motor proficiency and perceptions of competence did not in turn influence kindergarten children's participation in physical activity. These findings support concepts of developmental differences in the structure of the self-perception system.

The relationship between angiotensin-converting enzyme (ACE) insertion (I) / deletion (D) polymorphism, serum ACE activity and bone mineral density (BMD) in older Chinese.

PubMed

Zhang, Ya-Feng; Wang, Hong; Cheng, Qiong; Qin, Ling; Tang, Nelson Ls; Leung, Ping-Chong; Kwok, Timothy Cy

2017-01-01

In this study, we set out to investigate the relationship between angiotensin-converting enzyme ( ACE) I/D polymorphism, serum ACE activity and bone mineral density (BMD) in older Chinese. A standardized, structured, face-to-face interview was performed to collect demographic information. BMD was measured using dual-energy X-ray absorptiometry (DXA). I/D genotypes of ACE were determined by polymerase chain reaction (PCR) amplification. Serum ACE activity was determined photometrically by a commercially available kinetic kit. Multiple linear regression analysis was used to examine the relationship between ACE I/D polymorphism, serum ACE activity and BMD. A total of 1567 males and 1760 females were selected for analyzing the relationship between ACE I/D polymorphism and BMD. There was no significant difference in spine BMD, total hip BMD and femur neck BMD among different ACE I/D genotypes both in males and females. A total of 1699 males and 1739 females were selected for analyzing the relationship between serum ACE activity and BMD. There was also no significant difference in spine BMD, total hip BMD and femur neck BMD among different serum ACE activity groups both in males and females. There was no relationship between ACE I/D polymorphism, serum ACE activity and BMD in older Chinese.

Influence of lipophilicity in O-acyl and O-alkyl derivatives of juglone and lawsone: a structure-activity relationship study in the search for natural herbicide models.

PubMed

Durán, Alexandra G; Chinchilla, Nuria; Molinillo, José Mg; Macías, Francisco A

2018-03-01

Naphthoquinones are known for their broad range of biological activities. Given the increasing demands of consumers in relation to food quality and growing concerns about the impact of synthetic herbicides, it is necessary to search for new agrochemicals. Natural products and allelopathy provide new alternatives for the development of pesticides with lower toxicity and greater environmental compatibility. A structure-activity relationship to evaluate the effect of bioavailability was performed. A total of 44 O-acyl and O-alkyl derivatives of juglone and lawsone with different linear chain lengths were prepared. These compounds were tested on etiolated wheat coleoptiles, standard target species (STS) and four weeds, Echinochloa crus-galli L., Lolium rigidum Gaud., Lolium perenne L. and Avena fatua L. The results showed a strong influence of lipophilicity and, in most cases, the data fitted a logP-dependent quadratic mathematical model. The effects produced were mostly stunting and necrosis caused by growth inhibition. The potential structure and activity behaviour is described. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

The Prototype of Indicators of a Responsive Partner Shapes Information Processing: A False Recognition Study.

PubMed

Turan, Bulent

2016-01-01

When judging whether a relationship partner can be counted on to "be there" when needed, people may draw upon knowledge structures to process relevant information. We examined one such knowledge structure using the prototype methodology: indicators of a partner who is likely to be there when needed. In the first study (N = 91), the structure, content, and reliability of the prototype of indicators were examined. Then, using a false recognition study (N = 77), we demonstrated that once activated, the prototype of indicators of a partner who is likely to be there when needed affects information processing. Thus, the prototype of indicators may shape how people process support-relevant information in everyday life, affecting relationship outcomes. Using this knowledge structure may help a person process relevant information quickly and with cognitive economy. However, it may also lead to biases in judgments in certain situations.

Tubulin polymerization-stimulating activity of Ganoderma triterpenoids.

PubMed

Kohno, Toshitaka; Hai-Bang, Tran; Zhu, Qinchang; Amen, Yhiya; Sakamoto, Seiichi; Tanaka, Hiroyuki; Morimoto, Satoshi; Shimizu, Kuniyoshi

2017-04-01

Tubulin polymerization is an important target for anticancer therapies. Even though the potential of Ganoderma triterpenoids against various cancer targets had been well documented, studies on their tubulin polymerization-stimulating activity are scarce. This study was conducted to evaluate the effect of Ganoderma triterpenoids on tubulin polymerization. A total of twenty-four compounds were investigated using an in vitro tubulin polymerization assay. Results showed that most of the studied triterpenoids exhibited microtuble-stabilizing activity to different degrees. Among the investigated compounds, ganoderic acid T-Q, ganoderiol F, ganoderic acid S, ganodermanontriol and ganoderic acid TR were found to have the highest activities. A structure-activity relationship (SAR) analysis was performed. Extensive investigation of the SAR suggests the favorable structural features for the tubulin polymerization-stimulating activity of lanostane triterpenes. These findings would be helpful for further studies on the potential mechanisms of the anticancer activity of Ganoderma triterpenoids and give some indications on the design of tubulin-targeting anticancer agents.

Cinnamaldehyde and related phenylpropanoids, natural repellents and insecticides against Sitophilus zeamais (Motsch.). A chemical structure-bioactivity relationship.

PubMed

Zaio, Yésica P; Gatti, Gerardo; Ponce, Andrés A; Saavedra Larralde, Natalia A; Martinez, María J; Zunino, María P; Zygadlo, Julio A

2018-05-13

Insecticidal activity and repellent effects on adults of Sitophilus zeamais of 12 cinnamaldehyde-related compounds was evaluated by contact toxicity bioassays and a two-choice olfactometer, respectively. To determine non-toxicity in mammals, additionally, body weight, serum biochemical profiles, liver weight, physiological parameters, sperm motility and histopathological data were obtained as complementary information in C57BL/6 mice, treated with the best natural compound. Based on 24h LC 95 and LC 50 values, alpha-methyl-cinnamaldehyde and cinnamaldehyde, respectively, exhibited better insecticidal activity than the other compounds. The best repellent effect was observed with alpha-bromo-cinnamaldehyde, which even repelled at the lowest concentration studied (0.28 μM). The evaluation of a quantitative structure-activity relationship showed a linear relationship between the LC 50 values for adult weevil toxicity and dipolo with Q (difference between orbital electronegativity carbon 1 and orbital electronegativity carbon 3 of the molecule) values in cinnamaldehyde-related compounds. In addition, the polar surface and Log P descriptors also revealed a linear relationship with the S. zeamais repellent effect for cinnamaldehyde analogues. Besides, cinnamaldehyde did not show toxicity in the parameters evaluated in mice. From the phenylpropanoid components studied, the natural compound which had the best insecticidal and repellent activity against S. zeamais was cinnamaldehyde and presented no mammalian toxicity. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Partial contribution of Rho-kinase inhibition to the bioactivity of Ganoderma lingzhi and its isolated compounds: insights on discovery of natural Rho-kinase inhibitors.

PubMed

Amen, Yhiya; Zhu, Qinchang; Tran, Hai-Bang; Afifi, Mohamed S; Halim, Ahmed F; Ashour, Ahmed; Shimizu, Kuniyoshi

2017-04-01

Recent studies identified Rho-kinase enzymes (ROCK-I and ROCK-II) as important targets that are involved in a variety of diseases. Synthetic Rho-kinase inhibitors have emerged as potential therapeutic agents to treat disorders such as hypertension, stroke, cancer, diabetes, glaucoma, etc. Our study is the first to screen the total ethanol extract of the medicinal mushroom Ganoderma lingzhi with thirty-five compounds for Rho-kinase inhibitory activity. Moreover, a molecular binding experiment was designed to investigate the binding affinity of the compounds at the active sites of Rho-kinase enzymes. The structure-activity relationship analysis was investigated. Our results suggest that the traditional uses of G. lingzhi might be in part due to the ROCK-I and ROCK-II inhibitory potential of this mushroom. Structure-activity relationship studies revealed some interesting features of the lanostane triterpenes that potentiate their Rho-kinase inhibition. These findings would be helpful for further studies on the design of Rho-kinase inhibitors from natural sources and open the door for contributions from other researchers for optimizing the development of natural Rho-kinase inhibitors.

Verbal Memory in Parkinson’s Disease: A Combined DTI and fMRI Study

PubMed Central

Lucas-Jiménez, Olaia; Díez-Cirarda, María; Ojeda, Natalia; Peña, Javier; Cabrera-Zubizarreta, Alberto; Ibarretxe-Bilbao, Naroa

2015-01-01

Background: While significant progress has been made to determine the functional role of specific gray matter areas underlying verbal memory in Parkinson’s disease (PD), very little is known about the relationship between these regions and their underlying white matter structures. Objective: The objectives of this study were (1) to investigate verbal memory, fractional anisotropy and brain activation differences between PD patients and healthy controls (HC), (2) to explore the neuroanatomical and neurofunctional correlates of verbal memory in PD, and (3) to investigate the relationship between these neuroanatomical and neurofunctional verbal memory correlates in PD. Methods: Functional magnetic resonance imaging (fMRI) while performing a verbal memory paradigm and diffusion tensor imaging data (DTI), were acquired in 37 PD patients and 15 age-, sex-, and education-matched HC. Results: PD patients showed verbal recognition memory impairment, lower fractional anisotropy in the anterior cingulate tract, and lower brain activation in the inferior orbitofrontal cortex compared to HC. Brain activation in the inferior orbitofrontal cortex correlated significantly with verbal recognition memory impairment in PD patients. In addition, a relationship between brain activation in the inferior orbitofrontal cortex and fractional anisotropy of the uncinate fasciculus was found in PD. Conclusions: These results reveal that deficits in verbal memory in PD are accompanied by functional brain activation changes, but also have specific structural correlates related to white matter microstructural integrity. PMID:27070003

Research and Teaching: Use of Toulmin's Argumentation Scheme for Student Discourse to Gain Insight about Guided Inquiry Activities in College Chemistry

ERIC Educational Resources Information Center

Kulatunga, Ushiri; Moog, Richard S.; Lewis, Jennifer E.

2014-01-01

Although student production of arguments in group learning environments has been shown to promote scientific reasoning and understanding of science concepts, little previous work has examined the relationship of the structure of curricular materials to the production of argumentation. In this study, we examined this relationship for a collection…

Tree microhabitat structures as indicators of biodiversity in Douglas-fir forests of different stand ages and management histories in the Pacific Northwest, U.S.A.

Treesearch

Alexa K. Michel; Susanne Winter

2009-01-01

In this study, microhabitat structures in Douglas-fir (Pseudotsuga menziesii) forests were defined and their frequency and abundance in natural stands and stands of varying active management histories and stand ages was compared. Indicator microhabitat structures for natural forests were determined and the relationship of the abundance of...

Inositolphosphoglycan mediators structurally related to glycosyl phosphatidylinositol anchors: synthesis, structure and biological activity.

PubMed

Martín-Lomas, M; Khiar, N; García, S; Koessler, J L; Nieto, P M; Rademacher, T W

2000-10-02

The preparation of the pseudopentasaccharide 1a, an inositol-phosphoglycan (IPG) that contains the conserved linear structure of glycosyl phosphatidylinositol anchors (GPI anchors), was carried out by using a highly convergent 2+3-block synthesis approach which involves imidate and sulfoxide glycosylation reactions. The preferred solution conformation of this structure was determined by using NMR spectroscopy and molecular dynamics simulations prior to carrying out quantitative structure--activity relationship studies in connection with the insulin signalling process. The ability of 1a to stimulate lipogenesis in rat adipocytes as well as to inhibit cAMP dependent protein kinase and to activate pyruvate dehydrogenase phosphatase was investigated. Compound 1a did not show any significant activity, which may be taken as a strong indication that the GPI anchors are not the precursors of the IPG mediators.

Structure-Activity Relationships of 33 Piperidines as Toxicants Against Female Adults of Aedes aegypti (Diptera: Culicidae)

DTIC Science & Technology

2007-03-01

alkaloid piperine and 12 syn- thetic derivatives have been evaluated against epimas- tigote and amastigote forms of the protozoan parasite Trypanosoma...O. Kris- tiansen, P. Maienfisch, A. Pascual, and A. Rindlisbacher. 2001. Synthesis and structure-activity relationships of benzophenone hydrazone...Am. J. Trop. Med. Hyg. 22: 124Ð 129. Creemer, L. C., H. A. Kirst, J.W. Paschal, and T. V.Worden. 2000. Synthesis and insecticidal activity of spinosyn

Insights into the structural/conformational requirements of cytotoxic oxadiazoles as potential chemotherapeutic target binding agents

NASA Astrophysics Data System (ADS)

Alikhani, Radin; Razzaghi-Asl, Nima; Ramazani, Ali; Hosseinzadeh, Zahra

2018-07-01

A few novel previously synthesized 2,5-disubstituted 1,3,4-oxadiazoles with cytotoxic activity (1-17) were subjected to combined docking/quantum mechanical studies against chemotherapeutic targets. Selected macromolecular targets were those that were previously known to be inhibited by 1,3,4-oxadiazoles. Within this work, favorable binding modes/affinities of the oxadiazoles toward validated cancer targets were elucidated. Some oxadiazole structures exhibited ΔGbs comparable to or stronger than crystallographic ligands that were previously demonstrated to inhibit such targets. On the basis of obtained results, a general structure activity/binding relationship (SAR/SBR) was developed and a few 2,5-disubstituted 1,3,4-oxadiazole structures were proposed and virtually validated as potential cytotoxic candidates. To get more insight into structure binding relationship of candidate molecules within best correlated targets, docked conformation of the best in silico in vitro correlated oxadiazole structure was analyzed in terms of intermolecular binding energy components by functional B3LYP in association with split valence basis set using polarization functions (Def2-SVP). We believe that such modeling studies may be complementary to our previous results on the synthesis and cytotoxicity assessment of novel 1,3,4-oxadiazole derivatives through extending the scope of privileged structures toward designing new potential anti-tumor compounds.

GirlPOWER! Strengthening Mentoring Relationships through a Structured, Gender-Specific Program

ERIC Educational Resources Information Center

Pryce, Julia M.; Silverthorn, Naida; Sanchez, Bernadette; DuBois, David L.

2010-01-01

The authors examine GirlPOWER! an innovative program that uses structure and group-based activities to enhance one-to-one mentoring relationships for young adolescent girls from the perspective of the focus, purpose, and authorship dimensions of mentoring relationships that Karcher and Nakkula described. The discussion draws on several sources of…

4(1H)-Pyridone and 4(1H)-Quinolone Derivatives as Antimalarials with Erythrocytic, Exoerythrocytic, and Transmission Blocking Activities

PubMed Central

Monastyrskyi, Andrii; Kyle, Dennis E.; Manetsch, Roman

2015-01-01

Infectious diseases are the second leading cause of deaths in the world with malaria being responsible for approximately the same amount of deaths as cancer in 2012. Despite the success in malaria prevention and control measures decreasing the disease mortality rate by 45% since 2000, the development of single-dose therapeutics with radical cure potential is required to completely eradicate this deadly condition. Targeting multiple stages of the malaria parasite is becoming a primary requirement for new candidates in antimalarial drug discovery and development. Recently, 4(1H)-pyridone, 4(1H)-quinolone, 1,2,3,4-tetrahydroacridone, and phenoxyethoxy-4(1H)-quinolone chemotypes have been shown to be antimalarials with blood stage activity, liver stage activity, and transmission blocking activity. Advancements in structure-activity relationship and structure-property relationship studies, biological evaluation in vitro and in vivo, as well as pharmacokinetics of the 4(1H)-pyridone and 4(1H)-quinolone chemotypes will be discussed. PMID:25116582

Characterizing structure connectivity correlation with the default mode network in Alzheimer's patients and normal controls

NASA Astrophysics Data System (ADS)

Guo, Jia; Xu, Peng; Song, Chao; Yao, Li; Zhao, Xiaojie

2012-03-01

Magnetic resonance diffusion tensor imaging (DTI) is a kind of effective measure to do non-invasive investigation on brain fiber structure at present. Studies of fiber tracking based on DTI showed that there was structural connection of white matter fiber among the nodes of resting-state functional network, denoting that the connection of white matter was the basis of gray matter regions in functional network. Nevertheless, relationship between these structure connectivity regions and functional network has not been clearly indicated. Moreover, research of fMRI found that activation of default mode network (DMN) in Alzheimer's disease (AD) was significantly descended, especially in hippocampus and posterior cingulated cortex (PCC). The relationship between this change of DMN activity and structural connection among functional networks needs further research. In this study, fast marching tractography (FMT) algorithm was adopted to quantitative calculate fiber connectivity value between regions, and hippocampus and PCC which were two important regions in DMN related with AD were selected to compute white matter connection region between them in elderly normal control (NC) and AD patient. The fiber connectivity value was extracted to do the correlation analysis with activity intensity of DMN. Results showed that, between PCC and hippocampus of NC, there exited region with significant high connectivity value of white matter fiber whose performance has relatively strong correlation with the activity of DMN, while there was no significant white matter connection region between them for AD patient which might be related with reduced network activation in these two regions of AD.

The structure-activity relationship in herbicidal monosubstituted sulfonylureas

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

Li, Zheng-Ming; Ma, Yi; Guddat, Luke

The herbicide sulfonylurea (SU) belongs to one of the most important class of herbicides worldwide. It is well known for its ecofriendly, extreme low toxicity towards mammals and ultralow dosage application. The original inventor, G Levitt, set out structure-activity relationship (SAR) guidelines for SU structural design to attain superhigh bioactivity. A new approach to SU molecular design has been developed. After the analysis of scores of SU products by X-ray diffraction methodology and after greenhouse herbicidal screening of 900 novel SU structures synthesized in the authors laboratory, it was found that several SU structures containing a monosubstituted pyrimidine moiety retainmore » excellent herbicidal characteristics, which has led to partial revision of the Levitt guidelines. Among the novel SU molecules, monosulfuron and monosulfuron-ester have been developed into two new herbicides that have been officially approved for field application and applied in millet and wheat fields in China. A systematic structural study of the new substrate-target complex and the relative mode of action in comparison with conventional SU has been carried out. A new mode of action has been postulated.« less

Calcitonin-typical suppression of osteoclastic activity by amphioxus calcitonin superfamily peptides and insights into the evolutionary conservation and diversity of their structures.

PubMed

Sekiguchi, Toshio; Shiraishi, Akira; Satake, Honoo; Kuwasako, Kenji; Takahashi, Hiroki; Sato, Masayuki; Urata, Makoto; Wada, Shuichi; Endo, Masato; Ikari, Takahiro; Hattori, Atsuhiko; Srivastav, Ajai K; Suzuki, Nobuo

2017-05-15

Calcitonin (CT) is a hormone that decreases serum calcium level by suppressing osteoclastic activity in the vertebrate bone. In vertebrates, the structure-function relationship of CTs has been studied extensively. We recently identified three CT superfamily peptides, Bf-CTFP1 to 3, and clarified the molecular and functional characteristics of their receptor and receptor activity-modifying protein in amphioxus, Branchiostoma floridae. However, the CT activity of Bf-CTFPs has yet to be investigated. In the present study, a functional analysis of Bf-CTFPs was performed using goldfish scales having both osteoclasts and osteoblasts. All Bf-CTFPs suppressed osteoclastic activity via a goldfish CT receptor. Although the primary amino acid sequences of the Bf-CTFPs showed low sequence similarity to vertebrate CTs, Bf-CTFP1 to 3 share three amino acids, Thr 25 , Thr 27 , and Pro 32 -NH 2 , that are required for receptor binding, with salmon CT. Moreover, homology model analysis revealed that the Bf-CTFPs form alpha-helical structures. The alpha-helical position and length of Bf-CTFP1 and 2 were conserved with those of a highly potent ligand, teleost CT. Interestingly, the composition of the alpha-helix of Bf-CTFP3 differed from those of teleost CT, despite that the action of Bf-CTFP3 on goldfish scales was the same as that of Bf-CTFP1 and 2. Collectively, the present study provides new insights into the structure-function relationship of CT and its functional evolution in chordates. Copyright © 2017 Elsevier Inc. All rights reserved.

Novel 1,4-naphthoquinone-based sulfonamides: Synthesis, QSAR, anticancer and antimalarial studies.

PubMed

Pingaew, Ratchanok; Prachayasittikul, Veda; Worachartcheewan, Apilak; Nantasenamat, Chanin; Prachayasittikul, Supaluk; Ruchirawat, Somsak; Prachayasittikul, Virapong

2015-10-20

A novel series of 1,4-naphthoquinones (33-44) tethered by open and closed chain sulfonamide moieties were designed, synthesized and evaluated for their cytotoxic and antimalarial activities. All quinone-sulfonamide derivatives displayed a broad spectrum of cytotoxic activities against all of the tested cancer cell lines including HuCCA-1, HepG2, A549 and MOLT-3. Most quinones (33-36 and 38-43) exerted higher anticancer activity against HepG2 cell than that of the etoposide. The open chain analogs 36 and 42 were shown to be the most potent compounds. Notably, the restricted sulfonamide analog 38 with 6,7-dimethoxy groups exhibited the most potent antimalarial activity (IC₅₀ = 2.8 μM). Quantitative structure-activity relationships (QSAR) study was performed to reveal important chemical features governing the biological activities. Five constructed QSAR models provided acceptable predictive performance (Rcv 0.5647-0.9317 and RMSEcv 0.1231-0.2825). Four additional sets of structurally modified compounds were generated in silico (34a-34d, 36a-36k, 40a-40d and 42a-42k) in which their activities were predicted using the constructed QSAR models. A comprehensive discussion of the structure-activity relationships was made and a set of promising compounds (i.e., 33, 36, 38, 42, 36d, 36f, 42e, 42g and 42f) was suggested for further development as anticancer and antimalarial agents. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Novel inhibitors of IMPDH: a highly potent and selective quinolone-based series.

PubMed

Watterson, Scott H; Carlsen, Marianne; Dhar, T G Murali; Shen, Zhongqi; Pitts, William J; Guo, Junqing; Gu, Henry H; Norris, Derek; Chorba, John; Chen, Ping; Cheney, Daniel; Witmer, Mark; Fleener, Catherine A; Rouleau, Katherine; Townsend, Robert; Hollenbaugh, Diane L; Iwanowicz, Edwin J

2003-02-10

A series of novel quinolone-based small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH) was explored. The synthesis and the structure-activity relationships (SARs) derived from in vitro studies are described.

PLS-based quantitative structure-activity relationship for substituted benzamides of clebopride type. Application of experimental design in drug design.

PubMed

Norinder, U; Högberg, T

1992-04-01

The advantageous approach of using an experimentally designed training set as the basis for establishing a quantitative structure-activity relationship with good predictive capability is described. The training set was selected from a fractional factorial design scheme based on a principal component description of physico-chemical parameters of aromatic substituents. The derived model successfully predicts the activities of additional substituted benzamides of 6-methoxy-N-(4-piperidyl)salicylamide type. The major influence on activity of the 3-substituent is demonstrated.

Antimicrobial activity of 9-O-acyl- and 9-O-benzoyl-substituted berberrubines.

PubMed

Hong, S W; Kim, S H; Jeun, J A; Lee, S J; Kim, S U; Kim, J H

2000-05-01

In the course of a structure-activity relationship study on berberrubine derivatives, a series of compounds bearing 9-O-acyl-(4-6) and 9-O-benzoyl- (7) substituents was synthesized with the expectation of increasing the antimicrobial activity. One of the berberrubine derivatives, 9-lauroylberberrubine chloride was the most active against Gram-positive bacteria Enterococcus faecalis, Staphylococcus aureus, Staphylococcus epidermidis, Micrococcus luteus, Bacillus subtilis as well as the Gram-negative bacterium Klebsiella pneumoniae in comparison to berberine, the currently used antibiotic in clinic. This result suggested that the presence of lipophilic substituents of certain structures and sizes might be crucial for the optimal antimicrobial activity.

Structure-activity relationship and mechanism of action studies of manzamine analogues for the control of neuroinflammation and cerebral infections.

PubMed

Peng, Jiangnan; Kudrimoti, Sucheta; Prasanna, Sivaprakasam; Odde, Srinivas; Doerksen, Robert J; Pennaka, Hari K; Choo, Yeun-Mun; Rao, Karumanchi V; Tekwani, Babu L; Madgula, Vamsi; Khan, Shabana I; Wang, Bin; Mayer, Alejandro M S; Jacob, Melissa R; Tu, Lan Chun; Gertsch, Jürg; Hamann, Mark T

2010-01-14

Structure-activity relationship studies were carried out by chemical modification of manzamine A (1), 8-hydroxymanzamine A (2), manzamine F (14), and ircinal isolated from the sponge Acanthostrongylophora. The derived analogues were evaluated for antimalarial, antimicrobial, and antineuroinflammatory activities. Several modified products exhibited potent and improved in vitro antineuroinflammatory, antimicrobial, and antimalarial activity. 1 showed improved activity against malaria compared to chloroquine in both multi- and single-dose in vivo experiments. The significant antimalarial potential was revealed by a 100% cure rate of malaria in mice with one administration of 100 mg/kg of 1. The potent antineuroinflammatory activity of the manzamines will provide great benefit for the prevention and treatment of cerebral infections (e.g., Cryptococcus and Plasmodium). In addition, 1 was shown to permeate across the blood-brain barrier (BBB) in an in vitro model using a MDR-MDCK monolayer. Docking studies support that 2 binds to the ATP-noncompetitive pocket of glycogen synthesis kinase-3beta (GSK-3beta), which is a putative target of manzamines. On the basis of the results presented here, it will be possible to initiate rational drug design efforts around this natural product scaffold for the treatment of several different diseases.

Inuloxins A-D and derivatives as antileishmanial agents: structure-activity relationship study

USDA-ARS?s Scientific Manuscript database

Inuloxins A-D (1-4) and a-costic acid (5), the phytotoxic compounds previously isolated from Inula viscosa, as well as synthetic derivatives of inuloxin A (compounds 6-10), inuloxin C (compound 11) and inuloxin D (compound 12) were tested in vitro for their activity against Leishmania donovani, the ...

Structure-Antibacterial Activity Relationships of Imidazolium-Type Ionic Liquid Monomers, Poly(ionic liquids) and Poly(ionic liquid) Membranes: Effect of Alkyl Chain Length and Cations.

PubMed

Zheng, Zhiqiang; Xu, Qiming; Guo, Jiangna; Qin, Jing; Mao, Hailei; Wang, Bin; Yan, Feng

2016-05-25

The structure-antibacterial activity relationship between the small molecular compounds and polymers are still elusive. Here, imidazolium-type ionic liquid (IL) monomers and their corresponding poly(ionic liquids) (PILs) and poly(ionic liquid) membranes were synthesized. The effect of chemical structure, including carbon chain length of substitution at the N3 position and charge density of cations (mono- or bis-imidazolium) on the antimicrobial activities against both Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) was investigated by determination of minimum inhibitory concentration (MIC). The antibacterial activities of both ILs and PILs were improved with the increase of the alkyl chain length and higher charge density (bis-cations) of imidazolium cations. Moreover, PILs exhibited lower MIC values relative to the IL monomers. However, the antibacterial activities of PIL membranes showed no correlation to those of their analogous small molecule IL monomers and PILs, which increased with the charge density (bis-cations) while decreasing with the increase of alkyl chain length. The results indicated that antibacterial property studies on small molecules and homopolymers may not provide a solid basis for evaluating that in corresponding polymer membranes.

Structure-Activity Relationship Studies Using Natural and Synthetic Okadaic Acid/Dinophysistoxin Toxins.

PubMed

Twiner, Michael J; Doucette, Gregory J; Pang, Yucheng; Fang, Chao; Forsyth, Craig J; Miles, Christopher O

2016-11-04

Okadaic acid (OA) and the closely related dinophysistoxins (DTXs) are algal toxins that accumulate in shellfish and are known serine/threonine protein phosphatase (ser/thr PP) inhibitors. Phosphatases are important modulators of enzyme activity and cell signaling pathways. However, the interactions between the OA/DTX toxins and phosphatases are not fully understood. This study sought to identify phosphatase targets and characterize their structure-activity relationships (SAR) with these algal toxins using a combination of phosphatase activity and cytotoxicity assays. Preliminary screening of 21 human and yeast phosphatases indicated that only three ser/thr PPs (PP2a, PP1, PP5) were inhibited by physiologically saturating concentrations of DTX2 (200 nM). SAR studies employed naturally-isolated OA, DTX1, and DTX2, which vary in degree and/or position of methylation, in addition to synthetic 2- epi -DTX2. OA/DTX analogs induced cytotoxicity and inhibited PP activity with a relatively conserved order of potency: OA = DTX1 ≥ DTX2 > 2- epi -DTX. The PPs were also differentially inhibited with sensitivities of PP2a > PP5 > PP1. These findings demonstrate that small variations in OA/DTX toxin structures, particularly at the head region (i.e., C1/C2), result in significant changes in toxicological potency, whereas changes in methylation at C31 and C35 (tail region) only mildly affect potency. In addition to this being the first study to extensively test OA/DTX analogs' activities towards PP5, these data will be helpful for accurately determining toxic equivalence factors (TEFs), facilitating molecular modeling efforts, and developing highly selective phosphatase inhibitors.

Discovery of Benzofuran Derivatives that Collaborate with Insulin-Like Growth Factor 1 (IGF-1) to Promote Neuroprotection.

PubMed

Wakabayashi, Takeshi; Tokunaga, Norihito; Tokumaru, Kazuyuki; Ohra, Taiichi; Koyama, Nobuyuki; Hayashi, Satoru; Yamada, Ryuji; Shirasaki, Mikio; Inui, Yoshitaka; Tsukamoto, Tetsuya

2016-05-26

A series of benzofuran derivatives with neuroprotective activity in collaboration with IGF-1 was discovered using a newly developed cell-based assay involving primary neural cells prepared from rat hippocampal and cerebral cortical tissues. A structure-activity relationship study identified compound 8 as exhibiting potent activity and brain penetrability. An in vitro pharmacological study demonstrated that although IGF-1 and 8 individually exhibited the neuroprotective effect, the latter acted in collaboration with IGF-1 to enhance neuroprotective activity.

Design, synthesis and exploring the quantitative structure-activity relationship of some antioxidant flavonoid analogues.

PubMed

Das, Sreeparna; Mitra, Indrani; Batuta, Shaikh; Niharul Alam, Md; Roy, Kunal; Begum, Naznin Ara

2014-11-01

A series of flavonoid analogues were synthesized and screened for the in vitro antioxidant activity through their ability to quench 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical. The activity of these compounds, measured in comparison to the well-known standard antioxidants (29-32), their precursors (38-42) and other bioactive moieties (38-42) resembling partially the flavone skeleton was analyzed further to develop Quantitative Structure-Activity Relationship (QSAR) models using the Genetic Function Approximation (GFA) technique. Based on the essential structural requirements predicted by the QSAR models, some analogues were designed, synthesized and tested for activity. The predicted and experimental activities of these compounds were well correlated. Flavone analogue 20 was found to be the most potent antioxidant. Copyright © 2014 Elsevier Ltd. All rights reserved.

Quantitative Structure-Antifungal Activity Relationships for cinnamate derivatives.

PubMed

Saavedra, Laura M; Ruiz, Diego; Romanelli, Gustavo P; Duchowicz, Pablo R

2015-12-01

Quantitative Structure-Activity Relationships (QSAR) are established with the aim of analyzing the fungicidal activities of a set of 27 active cinnamate derivatives. The exploration of more than a thousand of constitutional, topological, geometrical and electronic molecular descriptors, which are calculated with Dragon software, leads to predictions of the growth inhibition on Pythium sp and Corticium rolfsii fungi species, in close agreement to the experimental values extracted from the literature. A set containing 21 new structurally related cinnamate compounds is prepared. The developed QSAR models are applied to predict the unknown fungicidal activity of this set, showing that cinnamates like 38, 28 and 42 are expected to be highly active for Pythium sp, while this is also predicted for 28 and 34 in C. rolfsii. Copyright © 2015 Elsevier Inc. All rights reserved.

The Structure–Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation

PubMed Central

Bow, Eric W.; Rimoldi, John M.

2016-01-01

The cannabinoids are members of a deceptively simple class of terpenophenolic secondary metabolites isolated from Cannabis sativa highlighted by (−)-Δ9-tetrahydrocannabinol (THC), eliciting distinct pharmacological effects mediated largely by cannabinoid receptor (CB1 or CB2) signaling. Since the initial discovery of THC and related cannabinoids, synthetic and semisynthetic classical cannabinoid analogs have been evaluated to help define receptor binding modes and structure–CB1/CB2 functional activity relationships. This perspective will examine the classical cannabinoids, with particular emphasis on the structure–activity relationship of five regions: C3 side chain, phenolic hydroxyl, aromatic A-ring, pyran B-ring, and cyclohexenyl C-ring. Cumulative structure–activity relationship studies to date have helped define the critical structural elements required for potency and selectivity toward CB1 and CB2 and, more importantly, ushered the discovery and development of contemporary nonclassical cannabinoid modulators with enhanced physicochemical and pharmacological profiles. PMID:27398024

Leisure activities are linked to mental health benefits by providing time structure: comparing employed, unemployed and homemakers

PubMed Central

Goodman, William K; Geiger, Ashley M; Wolf, Jutta M

2017-01-01

Background Unemployment has consistently been linked to negative mental health outcomes, emphasising the need to characterise the underlying mechanisms. The current study aimed at testing whether compared with other employment groups, fewer leisure activities observed in unemployment may contribute to elevated risk for negative mental health via loss of time structure. Methods Depressive symptoms (Center for Epidemiologic Studies Depression), leisure activities (exercise, self-focused, social), and time structure (Time Structure Questionnaire (TSQ)) were assessed cross-sectionally in 406 participants (unemployed=155, employed=140, homemakers=111) recruited through Amazon Mechanical Turk. Results Controlling for gender and age, structural equation modelling revealed time structure partially (employed, homemakers) and fully (unemployed) mediated the relationship between leisure activities and depressive symptoms. With the exception of differential effects for structured routines, all other TSQ factors (sense of purpose, present orientation, effective organisation and persistence) contributed significantly to all models. Conclusions These findings support the idea that especially for the unemployed, leisure activities impose their mental health benefits through increasing individuals’ perception of spending their time effectively. Social leisure activities that provide a sense of daily structure may thereby be a particularly promising low-cost intervention to improve mental health in this population. PMID:27298424

Discovery of an ultra-short linear antibacterial tetrapeptide with anti-MRSA activity from a structure-activity relationship study.

PubMed

Lau, Qiu Ying; Ng, Fui Mee; Cheong, Jin Wei Darryl; Yap, Yi Yong Alvin; Tan, Yoke Yan Fion; Jureen, Roland; Hill, Jeffrey; Chia, Cheng San Brian

2015-11-13

The overuse and misuse of antibiotics has resulted in the emergence of drug-resistant pathogenic bacteria, including meticillin-resistant Staphylococcus aureus (MRSA), the primary pathogen responsible for human skin and soft-tissue infections. Antibacterial peptides are known to kill bacteria by rapidly disrupting their membranes and are deemed plausible alternatives to conventional antibiotics. One advantage of their membrane-targeting mode of action is that bacteria are unlikely to develop resistance as changing their cell membrane structure and morphology would likely involve extensive genetic mutations. However, major concerns in using peptides as antibacterial drugs include their instability towards plasma proteases, toxicity towards human cells due to their membrane-targeting mode of action and high manufacturing cost. These concerns can be mitigated by developing peptides as topical agents, by the judicial selection of amino acids and developing very short peptides respectively. In this preliminary report, we reveal a linear, non-hemolytic tetrapeptide with rapid bactericidal activity against MRSA developed from a structure-activity relationship study based on the antimicrobial hexapeptide WRWRWR-NH2. Our finding opens promising avenues for the development of ultra-short antibacterials to treat multidrug-resistant MRSA skin and soft tissue infections. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Using Theoretical Descriptors in Structural Activity Relationships: 4. Molecular Orbital Basicity and Electrostatic Basicity

DTIC Science & Technology

1988-11-01

rates.6 The Hammet equation , also called the Linear Free Energy Relationship (LFER) because of the relationship of the Gibb’s Free Energy to the... equations for numerous biological and physicochemical properties. Linear Solvation Enery Relationship (LSER), a sub-set of QSAR have been used by...originates from thermodynamics, where Hammet recognized the relationship of structure to the Gibb’s Free Energy, and ultimately to equilibria and reaction

Substrate uptake and protein stability relationship in mammalian histidine decarboxylase.

PubMed

Pino-Angeles, A; Morreale, A; Negri, A; Sánchez-Jiménez, F; Moya-García, A A

2010-01-01

There is some evidence linking the substrate entrance in the active site of mammalian histidine decarboxylase and an increased stability against proteolytic degradation. In this work, we study the basis of this relationship by means of protein structure network analysis and molecular dynamics simulations. We find that the substrate binding to the active site influences the conformation of a flexible region sensible to proteolytic degradation and observe how formation of the Michaelis-Menten complex increases stability in the conformation of this region. (c) 2009 Wiley-Liss, Inc.

Application of 3D-QSAR in the rational design of receptor ligands and enzyme inhibitors.

PubMed

Mor, Marco; Rivara, Silvia; Lodola, Alessio; Lorenzi, Simone; Bordi, Fabrizio; Plazzi, Pier Vincenzo; Spadoni, Gilberto; Bedini, Annalida; Duranti, Andrea; Tontini, Andrea; Tarzia, Giorgio

2005-11-01

Quantitative structure-activity relationships (QSARs) are frequently employed in medicinal chemistry projects, both to rationalize structure-activity relationships (SAR) for known series of compounds and to help in the design of innovative structures endowed with desired pharmacological actions. As a difference from the so-called structure-based drug design tools, they do not require the knowledge of the biological target structure, but are based on the comparison of drug structural features, thus being defined ligand-based drug design tools. In the 3D-QSAR approach, structural descriptors are calculated from molecular models of the ligands, as interaction fields within a three-dimensional (3D) lattice of points surrounding the ligand structure. These descriptors are collected in a large X matrix, which is submitted to multivariate analysis to look for correlations with biological activity. Like for other QSARs, the reliability and usefulness of the correlation models depends on the validity of the assumptions and on the quality of the data. A careful selection of compounds and pharmacological data can improve the application of 3D-QSAR analysis in drug design. Some examples of the application of CoMFA and CoMSIA approaches to the SAR study and design of receptor or enzyme ligands is described, pointing the attention to the fields of melatonin receptor ligands and FAAH inhibitors.

Comparative pharmacodynamic analysis of imidazoline compounds using rat model of ocular mydriasis with a test of quantitative structure-activity relationships.

PubMed

Raczak-Gutknecht, Joanna; Nasal, Antoni; Frąckowiak, Teresa; Kornicka, Anita; Sączewski, Franciszek; Wawrzyniak, Renata; Kubik, Łukasz; Kaliszan, Roman

2017-09-10

Imidazol(in)e derivatives, having the chemical structure similar to clonidine, exert diverse pharmacological activities connected with their interactions with alpha2-adrenergic receptors, e.g. hypotension, bradycardia, sedation as well as antinociceptive, anxiolytic, antiarrhythmic, muscle relaxant and mydriatic effects. The mechanism of pupillary dilation observed after systemic administration of imidazol(in)es to rats, mice and cats depends on the stimulation of postsynaptic alpha2-adrenoceptors within the brain. It was proved that the central nervous system (CNS)-localized I1-imidazoline receptors are not engaged in those effects. It appeared interesting to analyze the CNS-mediated pharmacodynamics of imidazole(in)e agents in terms of their chromatographic and calculation chemistry-derived parameters. In the present study a systematic determination and comparative pharmacometric analysis of mydriatic effects in rats were performed on a series of 20 imidazol(in)e agents, composed of the well-known drugs and of the substances used in experimental pharmacology. The eye pupil dilatory activities of the compounds were assessed in anesthetized Wistar rats according to the established Koss method. Among twenty imidazol(in)e derivatives studied, 18 produced diverse dose-dependent mydriatic effects. In the quantitative structure-activity relationships (QSAR) analysis, the pharmacological data (half maximum mydriatic effect - ED 50 in μmol/kg) were considered along with the structural parameters of the agents from molecular modeling. The theoretically calculated lipophilicity parameters, CLOGP, of imidazol(in)es, as well as their lipophilicity parameters from HPLC, logk w , were also considered. The attempts to derive statistically significant QSAR equations for a full series of the agents under study were unsuccessful. However, for a subgroup of eight apparently structurally related imidazol(in)es a significant relationship between log(1/ED 50 ) and logk w values was obtained. The lack of "predictive" QSAR for the whole series of the structurally diverse agents is probably due to a complex mechanism of the ligand-alpha2-adrenergic receptor interactions, which are predominantly of a highly structurally specific polar nature. Such interactions are difficult to quantify with the established chemical structural descriptors, contrary to the less specific, molecular bulkiness-related interactions. Copyright © 2017 Elsevier B.V. All rights reserved.

G Protein-Coupled Estrogen Receptor (GPER) Agonist Dual Binding Mode Analyses toward Understanding of its Activation Mechanism: A Comparative Homology Modeling Approach.

PubMed

Arnatt, Christopher K; Zhang, Yan

2013-07-01

G protein-coupled estrogen receptor (GPER) has been shown to be important in several disease states such as estrogen sensitive cancers. While several selective ligands have been identified for the receptor, little is known about how they interact with GPER and how their structures influence their activity. Specifically, within one series of ligands, whose structure varied only at one position, the replacement of a hydrogen atom with an acetyl group changed a potent antagonist into a potent agonist. In this study, two GPER homology models were constructed based on the x-ray crystal structures of both the active and inactive β 2 -adrenergic receptors (β 2 AR) in an effort to characterize the differences of binding modes between agonists and antagonists to the receptor, and to understand their activity in relation to their structures. The knowledge attained in this study is expected to provide valuable information on GPER ligands structure activity relationship to benefit future rational design of potent agonists and antagonists of the receptor for potential therapeutic applications.

G Protein-Coupled Estrogen Receptor (GPER) Agonist Dual Binding Mode Analyses toward Understanding of its Activation Mechanism: A Comparative Homology Modeling Approach

PubMed Central

Arnatt, Christopher K.; Zhang, Yan

2015-01-01

G protein-coupled estrogen receptor (GPER) has been shown to be important in several disease states such as estrogen sensitive cancers. While several selective ligands have been identified for the receptor, little is known about how they interact with GPER and how their structures influence their activity. Specifically, within one series of ligands, whose structure varied only at one position, the replacement of a hydrogen atom with an acetyl group changed a potent antagonist into a potent agonist. In this study, two GPER homology models were constructed based on the x-ray crystal structures of both the active and inactive β2-adrenergic receptors (β2AR) in an effort to characterize the differences of binding modes between agonists and antagonists to the receptor, and to understand their activity in relation to their structures. The knowledge attained in this study is expected to provide valuable information on GPER ligands structure activity relationship to benefit future rational design of potent agonists and antagonists of the receptor for potential therapeutic applications. PMID:26229572

Theoretical and conformational studies of a series of cannabinoids

NASA Astrophysics Data System (ADS)

Da Silva, Albérico B. F.; Trsic, Milan

1995-11-01

The MNDO semi-empirical method is applied to the study of a series of cannabinoids with the aim of providing an improved understanding of the structure-activity relationship (SAR). The conformation of some groups that seem important in the biological activity (psychoactivity) of these compounds is characterized. Some electronic properties, such as atomic net charges and HOMO and LUMO energies, are correlated with the psychoactive effect.

Structure guided design of a series of selective pyrrolopyrimidinone MARK inhibitors

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

Katz, Jason D.; Haidle, Andrew; Childers, Kaleen K.

2017-01-01

The initial structure activity relationships around an isoindoline uHTS hit will be described. Information gleaned from ligand co-crystal structures allowed for rapid refinements in both MARK potency and kinase selectivity. These efforts allowed for the identification of a compound with properties suitable for use as an in vitro tool compound for validation studies on MARK as a viable target for Alzheimer’s disease.

1-[(3-Aryloxy-3-aryl)propyl]-1H-imidazoles, new imidazoles with potent activity against Candida albicans and dermatophytes. Synthesis, structure-activity relationship, and molecular modeling studies.

PubMed

La Regina, Giuseppe; D'Auria, Felicia Diodata; Tafi, Andrea; Piscitelli, Francesco; Olla, Stefania; Caporuscio, Fabiana; Nencioni, Lucia; Cirilli, Roberto; La Torre, Francesco; De Melo, Nadja Rodrigues; Kelly, Steven L; Lamb, David C; Artico, Marino; Botta, Maurizio; Palamara, Anna Teresa; Silvestri, Romano

2008-07-10

New 1-[(3-aryloxy-3-aryl)propyl]-1 H-imidazoles were synthesized and evaluated against Candida albicans and dermatophytes in order to develop structure-activity relationships (SARs). Against C. albicans the new imidazoles showed minimal inhibitory concentrations (MICs) comparable to those of ketoconazole, miconazole, and econazole, and were more potent than fluconazole. Several derivatives ( 10, 12, 14, 18- 20, 24, 28, 29, 30, and 34) turned out to be potent inhibitors of C. albicans strains resistant to fluconazole, with MIC values less than 10 microg/mL. Against dermatophytes strains, compounds 20, 25, and 33 (MIC

Combinatorial QSAR Modeling of Rat Acute Toxicity by Oral Exposure

EPA Science Inventory

Quantitative Structure-Activity Relationship (QSAR) toxicity models have become popular tools for identifying potential toxic compounds and prioritizing candidates for animal toxicity tests. However, few QSAR studies have successfully modeled large, diverse mammalian toxicity end...

Relationship between structure and P-glycoprotein inhibitory activity of dimeric peptides related to the Dmt-Tic pharmacophore.

PubMed

Ambo, Akihiro; Ohkatsu, Hiromichi; Minamizawa, Motoko; Watanabe, Hideko; Sugawara, Shigeki; Nitta, Kazuo; Tsuda, Yuko; Okada, Yoshio; Sasaki, Yusuke

2012-03-15

To develop novel inhibitors of P-glycoprotein (P-gp), dimeric peptides related to an opioid peptide containing the Dmt-Tic pharmacophore were synthesized and their P-gp inhibitory activities were analyzed. Of the 30 analogs synthesized, N(α),N(ε)-[(CH(3))(2)Mle-Tic](2)Lys-NH(2) and its D-Lys analog were found to exhibit potent P-gp inhibitory activity, twice that of verapamil, in doxorubicin-resistant K562 cells. Structure-activity studies indicated that the correct hydrophobicity and spacer length between two aromatic rings are important structural elements in this series of analogs for inhibition of P-gp. Copyright © 2012 Elsevier Ltd. All rights reserved.

The neurobiology of pain, affect and hypnosis.

PubMed

Feldman, Jeffrey B

2004-01-01

Recent neuroimaging studies have used hypnotic suggestion to distinguish the brain structures most associated with the sensory and affective dimensions of pain. This paper reviews studies that delineate the overlapping brain circuits involved in the processing of pain and emotions, and their relationship to autonomic arousal. Also examined are the replicated findings of reliable changes in the activation of specific brain structures and the deactivation of others associated with the induction of hypnosis. These differ from those parts of the brain involved in response to hypnotic suggestions. It is proposed that the activation of a portion of the prefrontal cortex in response to both hypnotic suggestions for decreased pain and to positive emotional experience might indicate a more general underlying mechanism. Great potential exists for further research to clarify the relationships among individual differences in reactivity to pain, emotion, and stress, and the possible role of such differences in the development of chronic pain.

Elephant behaviour and conservation: social relationships, the effects of poaching, and genetic tools for management.

PubMed

Archie, Elizabeth A; Chiyo, Patrick I

2012-02-01

Genetic tools are increasingly valuable for understanding the behaviour, evolution, and conservation of social species. In African elephants, for instance, genetic data provide basic information on the population genetic causes and consequences of social behaviour, and how human activities alter elephants' social and genetic structures. As such, African elephants provide a useful case study to understand the relationships between social behaviour and population genetic structure in a conservation framework. Here, we review three areas where genetic methods have made important contributions to elephant behavioural ecology and conservation: (1) understanding kin-based relationships in females and the effects of poaching on the adaptive value of elephant relationships, (2) understanding patterns of paternity in elephants and how poaching can alter these patterns, and (3) conservation genetic tools to census elusive populations, track ivory, and understand the behavioural ecology of crop-raiding. By comparing studies from populations that have experienced a range of poaching intensities, we find that human activities have a large effect on elephant behaviour and genetic structure. Poaching disrupts kin-based association patterns, decreases the quality of elephant social relationships, and increases male reproductive skew, with important consequences for population health and the maintenance of genetic diversity. In addition, we find that genetic tools to census populations or gather forensic information are almost always more accurate than non-genetic alternatives. These results contribute to a growing understanding of poaching on animal behaviour, and how genetic tools can be used to understand and conserve social species. © 2011 Blackwell Publishing Ltd.

Polyphenols, their metabolites and derivatives as drug leads.

PubMed

Almeida, Filipa A; Dos Santos, Cláudia Nunes; Ventura, Maria Rita

2018-05-15

In this non-comprehensive review, the potential of natural polyphenols as lead compounds for the design and synthesis of new molecules with potential application in several diseases was highlighted. Organic synthesis has been essential for the development of new analogues of naturally found polyphenols, providing a wide range of structural modifications for structure-activity relationship studies and improving or modulating the biological activity of the promising compounds. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Relationship between electronic properties and drug activity of seven quinoxaline compounds: A DFT study

NASA Astrophysics Data System (ADS)

Behzadi, Hadi; Roonasi, Payman; Assle taghipour, Khatoon; van der Spoel, David; Manzetti, Sergio

2015-07-01

The quantum chemical calculations at the DFT/B3LYP level of theory were carried out on seven quinoxaline compounds, which have been synthesized as anti-Mycobacterium tuberculosis agents. Three conformers were optimized for each compound and the lowest energy structure was found and used in further calculations. The electronic properties including EHOMO, ELUMO and related parameters as well as electron density around oxygen and nitrogen atoms were calculated for each compound. The relationship between the calculated electronic parameters and biological activity of the studied compounds were investigated. Six similar quinoxaline derivatives with possible more drug activity were suggested based on the calculated electronic descriptors. A mechanism was proposed and discussed based on the calculated electronic parameters and bond dissociation energies.

The Structure-Activity Relationship between Marine Algae Polysaccharides and Anti-Complement Activity

PubMed Central

Jin, Weihua; Zhang, Wenjing; Liang, Hongze; Zhang, Quanbin

2015-01-01

In this study, 33 different polysaccharides were prepared to investigate the structure-activity relationships between the polysaccharides, mainly from marine algae, and anti-complement activity in the classical pathway. Factors considered included extraction methods, fractionations, molecular weight, molar ratio of galactose to fucose, sulfate, uronic acid (UA) content, linkage, branching, and the type of monosaccharide. It was shown that the larger the molecular weights, the better the activities. The molar ratio of galactose (Gal) to fucose (Fuc) was a positive factor at a concentration lower than 10 µg/mL, while it had no effect at a concentration more than 10 µg/mL. In addition, sulfate was necessary; however, the sulfate content, the sulfate pattern, linkage and branching had no effect at a concentration of more than 10 µg/mL. Moreover, the type of monosaccharide had no effect. Laminaran and UA fractions had no activity; however, they could reduce the activity by decreasing the effective concentration of the active composition when they were mixed with the active compositions. The effect of the extraction methods could not be determined. Finally, it was observed that sulfated galactofucan showed good anti-complement activity after separation. PMID:26712768

Natural and Semisynthetic Analogues of Manadoperoxide B Reveal New Structural Requirements for Trypanocidal Activity

PubMed Central

Chianese, Giuseppina; Scala, Fernando; Calcinai, Barbara; Cerrano, Carlo; Dien, Henny A.; Kaiser, Marcel; Tasdemir, Deniz; Taglialatela-Scafati, Orazio

2013-01-01

Chemical analysis of the Indonesian sponge Plakortis cfr. lita afforded two new analogues of the potent trypanocidal agent manadoperoxide B (1), namely 12-isomanadoperoxide B (2) and manadoperoxidic acid B (3). These compounds were isolated along with a new short chain dicarboxylate monoester (4), bearing some interesting relationships with the polyketide endoperoxides found in this sponge. Some semi-synthetic analogues of manadoperoxide B (6–8) were prepared and evaluated for antitrypanosomal activity and cytotoxicity. These studies revealed crucial structure–activity relationships that should be taken into account in the design of optimized and simplified endoperoxyketal trypanocidal agents. PMID:23989650

An examination on the influence of small and medium enterprise (SME) stakeholder on green supply chain management practices

NASA Astrophysics Data System (ADS)

Shahlan, M. Z.; Sidek, A. A.; Suffian, S. A.; Hazza, M. H. F. A.; Daud, M. R. C.

2018-01-01

In this paper, climate change and global warming are the biggest current issues in the industrial sectors. The green supply chain managements (GSCM) is one of the crucial input to these issues. Effective GSCM can potentially secure the organization’s competitive advantage and improve the environmental performance of the network activities. In this study, the aim is to investigate and examine how a small and medium enterprises (SMEs) stakeholder pressure and top management influence green supply chain management practices. The study is further advance green supply chain management research in Malaysia focusing on SMEs manufacturing sector using structural equation modelling. Structural equation modelling is a multivariate statistical analysis technique used to examine structural relationship. It is the combination of factor analysis and multi regression analysis and used to analyse structural relationship between measure variable and latent factor. This research found that top management support and stakeholder pressure is the major influence for SMEs to adopt green supply chain management. The research also found that top management is fully mediate with the relationship between stakeholder pressure and monitoring supplier environmental performance.

Abnormal Structure–Function Relationship in Spasmodic Dysphonia

PubMed Central

Ludlow, Christy L.

2012-01-01

Spasmodic dysphonia (SD) is a primary focal dystonia characterized by involuntary spasms in the laryngeal muscles during speech production. Although recent studies have found abnormal brain function and white matter organization in SD, the extent of gray matter alterations, their structure–function relationships, and correlations with symptoms remain unknown. We compared gray matter volume (GMV) and cortical thickness (CT) in 40 SD patients and 40 controls using voxel-based morphometry and cortical distance estimates. These measures were examined for relationships with blood oxygen level–dependent signal change during symptomatic syllable production in 15 of the same patients. SD patients had increased GMV, CT, and brain activation in key structures of the speech control system, including the laryngeal sensorimotor cortex, inferior frontal gyrus (IFG), superior/middle temporal and supramarginal gyri, and in a structure commonly abnormal in other primary dystonias, the cerebellum. Among these regions, GMV, CT and activation of the IFG and cerebellum showed positive relationships with SD severity, while CT of the IFG correlated with SD duration. The left anterior insula was the only region with decreased CT, which also correlated with SD symptom severity. These findings provide evidence for coupling between structural and functional abnormalities at different levels within the speech production system in SD. PMID:21666131

Toxicity of ionic liquids: database and prediction via quantitative structure-activity relationship method.

PubMed

Zhao, Yongsheng; Zhao, Jihong; Huang, Ying; Zhou, Qing; Zhang, Xiangping; Zhang, Suojiang

2014-08-15

A comprehensive database on toxicity of ionic liquids (ILs) is established. The database includes over 4000 pieces of data. Based on the database, the relationship between IL's structure and its toxicity has been analyzed qualitatively. Furthermore, Quantitative Structure-Activity relationships (QSAR) model is conducted to predict the toxicities (EC50 values) of various ILs toward the Leukemia rat cell line IPC-81. Four parameters selected by the heuristic method (HM) are used to perform the studies of multiple linear regression (MLR) and support vector machine (SVM). The squared correlation coefficient (R(2)) and the root mean square error (RMSE) of training sets by two QSAR models are 0.918 and 0.959, 0.258 and 0.179, respectively. The prediction R(2) and RMSE of QSAR test sets by MLR model are 0.892 and 0.329, by SVM model are 0.958 and 0.234, respectively. The nonlinear model developed by SVM algorithm is much outperformed MLR, which indicates that SVM model is more reliable in the prediction of toxicity of ILs. This study shows that increasing the relative number of O atoms of molecules leads to decrease in the toxicity of ILs. Copyright © 2014 Elsevier B.V. All rights reserved.

Lack of Influence of Apolipoprotein E Status on Cognition or Brain Structure in Professional Fighters

PubMed Central

Miller, Justin B.; Rissman, Robert A.; Bernick, Charles B.

2017-01-01

Abstract The role of the apolipoprotein e4 allele in moderating cognitive and neuroanatomical degeneration following repeated traumatic brain injury is controversial. Here we sought to establish the presence or absence of such a moderating relationship in a prospective study of active and retired boxers and mixed martial arts fighters. Fighters (n = 193) underwent cognitive evaluations, interviews regarding fight history, MRI of the brain, and genetic testing. We used a series of moderator analyses to test for any relationship of apolipoprotein genotype on structural volumes of brain regions previously established to be smaller in those with the most fight exposure, and on cognitive abilities also established to be sensitive to fight exposure. No moderating relationship was detected in any of the analyses. The results of this study suggest that there is no impact of apolipoprotein genotype on the apparent negative association between exposure to professional fighting and brain structure volume or aspects of cognition. PMID:27245878

Relationship between Chemical Structure and Antimicrobial Activities of Isothiocyanates from Cruciferous Vegetables against Oral Pathogens.

PubMed

Ko, Mi-Ok; Kim, Mi-Bo; Lim, Sang-Bin

2016-12-28

We evaluated the potentials of 10 isothiocyanates (ITCs) from cruciferous vegetables and radish root hydrolysate for inhibiting the growth of oral pathogens, with an emphasis on assessing any structure-function relationship. Structural differences in ITCs impacted their antimicrobial activities against oral pathogens differently. The indolyl ITC (indol-3-carbinol) was the most potent inhibitor of the growth of oral pathogens, followed by aromatic ITCs (benzyl ITC (BITC) and phenylethyl ITC (PEITC)) and aliphatic ITCs (erucin, iberin, and sulforaphene). Sulforaphene, which is similar in structure, but has one double bond, showed higher antimicrobial activity than sulforaphane. Erucin, which has a thiol group, showed higher antimicrobial activity than sulforaphane, which has a sulfinyl group. BITC and iberin with a short chain exhibited higher antimicrobial potential than PEITC and sulforaphane with a longer chain, respectively. ITCs have strong antimicrobial activities and may be useful in the prevention and management of dental caries.

Modeling the relationship between physical activity and quality of life in menopausal-aged women: a cross-sectional study.

PubMed

Javadivala, Zeinab; Kousha, Ahmad; Allahverdipour, Hamid; Asghari Jafarabadi, Mohammad; Tallebian, Hossein

2013-09-17

The purpose of the present study was (a) to assess the relationship between physical activity and the intensity and duration of menopausal symptoms, (b) to investigate the relationship between physical activity and the four domains of health-related quality of life (HRQOL) and (c) to assess the relationship between physical activity and chronic diseases. This descriptive-analytical study that was conducted in Tabriz City, Iran. Data were collected in 2012 by personal home-based interviews, using structured questionnaires. All participants (n= 273), who were middle-aged (age range of 40-60 yr) were recruited from two of the 25 urban health service centers' clients, by clustered random sampling allocation. There was a positive significant relationship between Psychological, Social, and Environmental domains of HRQOL with physical activity (P<0.001). In addition, a negative significant relation was found between somatic complaints including sexual problems (P< 0.017) and vaginal dryness (P<0.030) as well as joint-muscular discomfort (P<0.018), and the level of physical activity. Diabetic (P<0.047) and women with history of heart disease (P<0.040) performed 2.670 and 3.548 hours more than who were not. Regular physical activity would be effective in decreasing menopausal symptoms as well as improving healthy aging and also physical activity promotion as a part of healthy life style promotion programs needs to be improved in communities where women are physically inactive. In addition, women need to be informed about importance of physical activity on their life which it leads to feel healthy aging and pre and post- menopausal stages.

Activity Structures and the Unfolding of Problem-Solving Actions in High-School Chemistry Classrooms

NASA Astrophysics Data System (ADS)

Criswell, Brett A.; Rushton, Greg T.

2014-02-01

In this paper, we argue for a more systematic approach for studying the relationship between classroom practices and scientific practices—an approach that will likely better support the systemic reforms being promoted in the Next Generation Science Standards in the USA and similar efforts in other countries. One component of that approach is looking at how the nature of the activity structure may influence the relative alignment between classroom and scientific practices. To that end, we build on previously published research related to the practices utilized by five high-school chemistry teachers as they enacted problem-solving activities in which students were likely to generate proposals that were not aligned with normative scientific understandings. In that prior work, our analysis had emphasized micro-level features of the talk interactions and how they related to the way students' ideas were explored; in the current paper, the analysis zooms out to consider the macro-level nature of the enactments associated with the activity structure of each lesson examined. Our data show that there were two general patterns to the activity structure across the 14 lessons scrutinized, and that each pattern had associated with it a constellation of features that impinged on the way the problem space was navigated. A key finding is that both activity structures (the expansive and the open) had features that aligned with scientific practices espoused in the Next Generation Science Standards—and both had features that were not aligned with those practices. We discuss the nature of these two structures, evidence of the relationship of each structure to key features of how the lessons unfolded, and the implications of these findings for both future research and the training of teachers.

Spectral mapping of brain functional connectivity from diffusion imaging.

PubMed

Becker, Cassiano O; Pequito, Sérgio; Pappas, George J; Miller, Michael B; Grafton, Scott T; Bassett, Danielle S; Preciado, Victor M

2018-01-23

Understanding the relationship between the dynamics of neural processes and the anatomical substrate of the brain is a central question in neuroscience. On the one hand, modern neuroimaging technologies, such as diffusion tensor imaging, can be used to construct structural graphs representing the architecture of white matter streamlines linking cortical and subcortical structures. On the other hand, temporal patterns of neural activity can be used to construct functional graphs representing temporal correlations between brain regions. Although some studies provide evidence that whole-brain functional connectivity is shaped by the underlying anatomy, the observed relationship between function and structure is weak, and the rules by which anatomy constrains brain dynamics remain elusive. In this article, we introduce a methodology to map the functional connectivity of a subject at rest from his or her structural graph. Using our methodology, we are able to systematically account for the role of structural walks in the formation of functional correlations. Furthermore, in our empirical evaluations, we observe that the eigenmodes of the mapped functional connectivity are associated with activity patterns associated with different cognitive systems.

Relationships between cortical myeloarchitecture and electrophysiological networks

PubMed Central

Hunt, Benjamin A. E.; Tewarie, Prejaas K.; Mougin, Olivier E.; Geades, Nicolas; Singh, Krish D.; Morris, Peter G.; Gowland, Penny A.; Brookes, Matthew J.

2016-01-01

The human brain relies upon the dynamic formation and dissolution of a hierarchy of functional networks to support ongoing cognition. However, how functional connectivities underlying such networks are supported by cortical microstructure remains poorly understood. Recent animal work has demonstrated that electrical activity promotes myelination. Inspired by this, we test a hypothesis that gray-matter myelin is related to electrophysiological connectivity. Using ultra-high field MRI and the principle of structural covariance, we derive a structural network showing how myelin density differs across cortical regions and how separate regions can exhibit similar myeloarchitecture. Building upon recent evidence that neural oscillations mediate connectivity, we use magnetoencephalography to elucidate networks that represent the major electrophysiological pathways of communication in the brain. Finally, we show that a significant relationship exists between our functional and structural networks; this relationship differs as a function of neural oscillatory frequency and becomes stronger when integrating oscillations over frequency bands. Our study sheds light on the way in which cortical microstructure supports functional networks. Further, it paves the way for future investigations of the gray-matter structure/function relationship and its breakdown in pathology. PMID:27830650

Structure-Property-Function Relationship in Humic Substances to Explain the Biological Activity in Plants

PubMed Central

García, Andrés Calderín; de Souza, Luiz Gilberto Ambrosio; Pereira, Marcos Gervasio; Castro, Rosane Nora; García-Mina, José María; Zonta, Everaldo; Lisboa, Francy Junior Gonçalves; Berbara, Ricardo Luis Louro

2016-01-01

Knowledge of the structure-property-function relationship of humic substances (HSs) is key for understanding their role in soil. Despite progress, studies on this topic are still under discussion. We analyzed 37 humic fractions with respect to their isotopic composition, structural characteristics, and properties responsible for stimulating plant root parameters. We showed that regardless of the source of origin of the carbon (C3 or C4), soil-extracted HSs and humic acids (HAs) are structurally similar to each other. The more labile and functionalized HS fraction is responsible for root emission, whereas the more recalcitrant and less functionalized HA fraction is related to root growth. Labile structures promote root stimulation at lower concentrations, while recalcitrant structures require higher concentrations to promote a similar stimulus. These findings show that lability and recalcitrance, which are derived properties of humic fractions, are related to the type and intensity of their bioactivity. In summary, the comparison of humic fractions allowed a better understanding of the relationship between the source of origin of plant carbon and the structure, properties, and type and intensity of the bioactivity of HSs in plants. In this study, scientific concepts are unified and the basis for the agronomic use of HSs is established. PMID:26862010

Anti-ulcer agents: chemical aspect of solving the problem

NASA Astrophysics Data System (ADS)

Rogoza, L. N.; Salakhutdinov, N. F.

2015-01-01

The data on chemical structures and specific activities of compounds functioning as histamine H2-receptor antagonists, H+/K+-ATPase inhibitors at the exchange sites of hydrogen ions (proton pump inhibitors) and potassium ions (K+-competitive acid blockers) published from 1990 to 2013 are surveyed. The antisecretory agents with studied cytoprotective activity or with additional therapeutic properties compensating for disorders of internal defence mechanisms are presented. A separate section is devoted to the drugs that prevent or mitigate the NSAID-induced intestinal damage. All of the considered structures are classified according to the type of biological mechanism of action. Some aspects of the structure-activity relationships for such compounds are considered. The bibliography includes 83 references.

Design and prediction of new anticoagulants as a selective Factor IXa inhibitor via three-dimensional quantitative structure-property relationships of amidinobenzothiophene derivatives.

PubMed

Gao, Jia-Suo; Tong, Xu-Peng; Chang, Yi-Qun; He, Yu-Xuan; Mei, Yu-Dan; Tan, Pei-Hong; Guo, Jia-Liang; Liao, Guo-Chao; Xiao, Gao-Keng; Chen, Wei-Min; Zhou, Shu-Feng; Sun, Ping-Hua

2015-01-01

Factor IXa (FIXa), a blood coagulation factor, is specifically inhibited at the initiation stage of the coagulation cascade, promising an excellent approach for developing selective and safe anticoagulants. Eighty-four amidinobenzothiophene antithrombotic derivatives targeting FIXa were selected to establish three-dimensional quantitative structure-activity relationship (3D-QSAR) and three-dimensional quantitative structure-selectivity relationship (3D-QSSR) models using comparative molecular field analysis and comparative similarity indices analysis methods. Internal and external cross-validation techniques were investigated as well as region focusing and bootstrapping. The satisfactory q (2) values of 0.753 and 0.770, and r (2) values of 0.940 and 0.965 for 3D-QSAR and 3D-QSSR, respectively, indicated that the models are available to predict both the inhibitory activity and selectivity on FIXa against Factor Xa, the activated status of Factor X. This work revealed that the steric, hydrophobic, and H-bond factors should appropriately be taken into account in future rational design, especially the modifications at the 2'-position of the benzene and the 6-position of the benzothiophene in the R group, providing helpful clues to design more active and selective FIXa inhibitors for the treatment of thrombosis. On the basis of the three-dimensional quantitative structure-property relationships, 16 new potent molecules have been designed and are predicted to be more active and selective than Compound 33, which has the best activity as reported in the literature.

Structure-activity relationship studies on a Trp dendrimer with dual activities against HIV and enterovirus A71. Modifications on the amino acid.

PubMed

Martínez-Gualda, Belén; Sun, Liang; Rivero-Buceta, Eva; Flores, Aida; Quesada, Ernesto; Balzarini, Jan; Noppen, Sam; Liekens, Sandra; Schols, Dominique; Neyts, Johan; Leyssen, Pieter; Mirabelli, Carmen; Camarasa, María-José; San-Félix, Ana

2017-03-01

We have recently described a new class of dendrimers with tryptophan (Trp) on the surface that show dual antiviral activities against HIV and EV71 enterovirus. The prototype compound of this family is a pentaerythritol derivative with 12 Trps on the periphery. Here we complete the structure-activity relationship studies of this family to identify key features that might be significant for the antiviral activity. With this aim, novel dendrimers containing different amino acids (aromatic and non-aromatic), tryptamine (a "decarboxylated" analogue of Trp) and N-methyl Trp on the periphery have been prepared. Dendrimer with N-Methyl Trp was the most active against HIV-1 and HIV-2 while dendrimer with tyrosine was endowed with the most potent antiviral activity against EV71. This tyrosine dendrimer proved to inhibit a large panel of EV71 clinical isolates (belonging to different clusters) in the low nanomolar/high picomolar range. In addition, a new synthetic procedure (convergent approach) has been developed for the synthesis of the prototype and some other dendrimers. This convergent approach proved more efficient (higher yields, easier purification) than the divergent approach previously reported. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Phylogenomics and sequence-structure-function relationships in the GmrSD family of Type IV restriction enzymes.

PubMed

Machnicka, Magdalena A; Kaminska, Katarzyna H; Dunin-Horkawicz, Stanislaw; Bujnicki, Janusz M

2015-10-23

GmrSD is a modification-dependent restriction endonuclease that specifically targets and cleaves glucosylated hydroxymethylcytosine (glc-HMC) modified DNA. It is encoded either as two separate single-domain GmrS and GmrD proteins or as a single protein carrying both domains. Previous studies suggested that GmrS acts as endonuclease and NTPase whereas GmrD binds DNA. In this work we applied homology detection, sequence conservation analysis, fold recognition and homology modeling methods to study sequence-structure-function relationships in the GmrSD restriction endonucleases family. We also analyzed the phylogeny and genomic context of the family members. Results of our comparative genomics study show that GmrS exhibits similarity to proteins from the ParB/Srx fold which can have both NTPase and nuclease activity. In contrast to the previous studies though, we attribute the nuclease activity also to GmrD as we found it to contain the HNH endonuclease motif. We revealed residues potentially important for structure and function in both domains. Moreover, we found that GmrSD systems exist predominantly as a fused, double-domain form rather than as a heterodimer and that their homologs are often encoded in regions enriched in defense and gene mobility-related elements. Finally, phylogenetic reconstructions of GmrS and GmrD domains revealed that they coevolved and only few GmrSD systems appear to be assembled from distantly related GmrS and GmrD components. Our study provides insight into sequence-structure-function relationships in the yet poorly characterized family of Type IV restriction enzymes. Comparative genomics allowed to propose possible role of GmrD domain in the function of the GmrSD enzyme and possible active sites of both GmrS and GmrD domains. Presented results can guide further experimental characterization of these enzymes.

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.

Advances in methods to characterize ligand-induced ionic lock and rotamer toggle molecular switch in G protein-coupled receptors.

PubMed

Xie, Xiang-Qun; Chowdhury, Ananda

2013-01-01

Structural biology of GPCRs has made significant progress upon recently developed technologies for GPCRs expression/purification and elucidation of GPCRs crystal structures. The crystal structures provide a snapshot of the receptor structural disposition of GPCRs itself or with cocrystallized ligands, and the results are congruent with biophysical and computer modeling studies reported about GPCRs conformational and dynamics flexibility, regulated activation, and the various stabilizing interactions, such as "molecular switches." The molecular switches generally constitute the most conserved domains within a particular GPCR superfamily. Often agonist-induced receptor activation proceeds by the disruption of majority of these interactions, while antagonist and inverse agonist act as blockers and structural stabilizers, respectively. Several elegant studies, particularly for the β2AR, have demonstrated the relationship between ligand structure, receptor conformational changes, and corresponding pharmacological outcomes. Thus, it is of great importance to understand GPCRs activation related to cell signaling pathways. Herein, we summarize the steps to produce functional GPCRs, generate suitably fluorescent labeled GPCRs and the procedure to use that to understand if ligand-induced activation can proceed by activation of the GPCRs via ionic lock switch and/or rotamer toggle switch mechanisms. Such understanding of ligand structure and mechanism of receptor activation will provide great insight toward uncovering newer pathways of GPCR activation and aid in structure-based drug design. Copyright © 2013 Elsevier Inc. All rights reserved.

Modeling the relationship between family home environment factors and parental health.

PubMed

Didericksen, Katharine Wickel; Berge, Jerica M

2015-06-01

Understanding parental health is an important part of understanding family health. Previous research suggests that family meals, familial relationship satisfaction, and family physical activity may separately be related to physical health. The current study aims to combine these variables into a structural equation model to determine the collective relationship they have with adult health within a sample of parents (n = 1,435). Most parents were married, White, and highly educated. The relationship between family meals and parental health was significant (β = -.07, t = -2.29, p < .05), with the full model having adequate fit and accounting for some of the overall variance in parental health. Familial relationship satisfaction and family physical activity were not found to be associated with parental health. Exploratory findings of the sample stratified by biological sex are described. Findings from the current study were consistent with a systemic perspective in that parents may have health benefits when they participate in family-level behavior (e.g., family meals). Additional areas for research and limitations to the current study are also discussed. (c) 2015 APA, all rights reserved).

Biomacromolecular quantitative structure-activity relationship (BioQSAR): a proof-of-concept study on the modeling, prediction and interpretation of protein-protein binding affinity.

PubMed

Zhou, Peng; Wang, Congcong; Tian, Feifei; Ren, Yanrong; Yang, Chao; Huang, Jian

2013-01-01

Quantitative structure-activity relationship (QSAR), a regression modeling methodology that establishes statistical correlation between structure feature and apparent behavior for a series of congeneric molecules quantitatively, has been widely used to evaluate the activity, toxicity and property of various small-molecule compounds such as drugs, toxicants and surfactants. However, it is surprising to see that such useful technique has only very limited applications to biomacromolecules, albeit the solved 3D atom-resolution structures of proteins, nucleic acids and their complexes have accumulated rapidly in past decades. Here, we present a proof-of-concept paradigm for the modeling, prediction and interpretation of the binding affinity of 144 sequence-nonredundant, structure-available and affinity-known protein complexes (Kastritis et al. Protein Sci 20:482-491, 2011) using a biomacromolecular QSAR (BioQSAR) scheme. We demonstrate that the modeling performance and predictive power of BioQSAR are comparable to or even better than that of traditional knowledge-based strategies, mechanism-type methods and empirical scoring algorithms, while BioQSAR possesses certain additional features compared to the traditional methods, such as adaptability, interpretability, deep-validation and high-efficiency. The BioQSAR scheme could be readily modified to infer the biological behavior and functions of other biomacromolecules, if their X-ray crystal structures, NMR conformation assemblies or computationally modeled structures are available.

Phytochemicals from Dodonaea viscosa and their antioxidant and anticholinesterase activities with structure-activity relationships.

PubMed

Muhammad, Akhtar; Tel-Çayan, Gülsen; Öztürk, Mehmet; Duru, Mehmet Emin; Nadeem, Said; Anis, Itrat; Ng, Seik Weng; Shah, Muhammad Raza

2016-09-01

Context Dodonaea viscosa (L.) Jacq (Sapindaceae) has been used in traditional medicine as antimalarial, antidiabetic and antibacterial agent, but further investigations are needed. Objective This study determines the antioxidant and anticholinesterase activities of six compounds (1-6) and two crystals (1A and 3A) isolated from D. viscosa, and discusses their structure-activity relationships. Materials and methods Antioxidant activity was evaluated using six complementary tests, i.e., β-carotene-linoleic acid; DPPH(•), ABTS(•+), superoxide scavenging, CUPRAC and metal chelating assays. Anticholinesterase activity was performed using the Elman method. Results Clerodane diterpenoids (1 and 2) and phenolics (3-6) - together with three crystals (1A, 3A and 7A) - were isolated from the aerial parts of D. viscosa. Compound 3A exhibited good antioxidant activity in DPPH (IC50: 27.44 ± 1.06 μM), superoxide (28.18 ± 1.35% inhibition at 100 μM) and CUPRAC (A0.5: 35.89 ± 0.09 μM) assays. Compound 5 (IC50: 11.02 ± 0.02 μM) indicated best activity in ABTS assay, and 6 (IC50: 14.30 ± 0.18 μM) in β-carotene-linoleic acid assay. Compounds 1 and 3 were also obtained in the crystal (1A and 3A) form. Both crystals showed antioxidant activity. Furthermore, crystal 3A was more active than 3 in all activity tests. Phenol 6 possessed moderate anticholinesterase activity against acetylcholinesterase and butyrylcholinesterase enzymes (IC50 values: 158.14 ± 1.65 and 111.60 ± 1.28 μM, respectively). Discussion and conclusion This is the first report on antioxidant and anticholinesterase activities of compounds 1, 2, 5, 6, 1A and 3A, and characterisation of 7A using XRD. Furthermore, the structure-activity relationships are also discussed in detail for the first time.

Synthesis, activity, and structure--activity relationship studies of novel cationic lipids for DNA transfer.

PubMed

Byk, G; Dubertret, C; Escriou, V; Frederic, M; Jaslin, G; Rangara, R; Pitard, B; Crouzet, J; Wils, P; Schwartz, B; Scherman, D

1998-01-15

We have designed and synthesized original cationic lipids for gene delivery. A synthetic method on solid support allowed easy access to unsymmetrically monofunctionalized polyamine building blocks of variable geometries. These polyamine building blocks were introduced into cationic lipids. To optimize the transfection efficiency in the novel series, we have carried out structure-activity relationship studies by introduction of variable-length lipids, of variable-length linkers between lipid and cationic moiety, and of substituted linkers. We introduce the concept of using the linkers within cationic lipids molecules as carriers of side groups harboring various functionalities (side chain entity), as assessed by the introduction of a library composed of cationic entities, additional lipid chains, targeting groups, and finally the molecular probes rhodamine and biotin for cellular traffic studies. The transfection activity of the products was assayed in vitro on Hela carcinoma, on NIH3T3, and on CV1 fibroblasts and in vivo on the Lewis Lung carcinoma model. Products from the series displayed high transfection activities. Results indicated that the introduction of a targeting side chain moiety into the cationic lipid is permitted. A primary physicochemical characterization of the DNA/lipid complexes was demonstrated with this leading compound. Selected products from the series are currently being developed for preclinical studies, and the labeled lipopolyamines can be used to study the intracellular traffic of DNA/cationic lipid complexes.

Novel coumarins and related copper complexes with biological activity: DNA binding, molecular docking and in vitro antiproliferative activity.

PubMed

Pivetta, Tiziana; Valletta, Elisa; Ferino, Giulio; Isaia, Francesco; Pani, Alessandra; Vascellari, Sarah; Castellano, Carlo; Demartin, Francesco; Cabiddu, Maria Grazia; Cadoni, Enzo

2017-12-01

Coumarins show biological activity and are widely exploited for their therapeutic effects. Although a great number of coumarins substituted by heterocyclic moieties have been prepared, few studies have been carried out on coumarins containing pyridine heterocycle, which is known to modulate their physiological activities. We prepared and characterized three novel 3-(pyridin-2-yl)coumarins and their corresponding copper(II) complexes. We extended our investigations also to three known similar coumarins, since no data about their biochemical activity was previously been reported. The antiproliferative activity of the studied compounds was tested against human derived tumor cell lines and one human normal cell line. The DNA binding constants were determined and docking studies with DNA carried out. Selected Quantitative Structure-Activity Relationship (QSAR) descriptors were calculated in order to relate a set of structural and topological descriptors of the studied compounds to their DNA interaction and cytotoxic activity. Copyright © 2017 Elsevier Inc. All rights reserved.

Design of an activity landscape view taking compound-based feature probabilities into account.

PubMed

Zhang, Bijun; Vogt, Martin; Bajorath, Jürgen

2014-09-01

Activity landscapes (ALs) of compound data sets are rationalized as graphical representations that integrate similarity and potency relationships between active compounds. ALs enable the visualization of structure-activity relationship (SAR) information and are thus computational tools of interest for medicinal chemistry. For AL generation, similarity and potency relationships are typically evaluated in a pairwise manner and major AL features are assessed at the level of compound pairs. In this study, we add a conditional probability formalism to AL design that makes it possible to quantify the probability of individual compounds to contribute to characteristic AL features. Making this information graphically accessible in a molecular network-based AL representation is shown to further increase AL information content and helps to quickly focus on SAR-informative compound subsets. This feature probability-based AL variant extends the current spectrum of AL representations for medicinal chemistry applications.

Brief Report: Association between Socio-Demographic Factors, Screen Media Usage and Physical Activity by Type of Day in Spanish Adolescents

ERIC Educational Resources Information Center

Devis-Devis, Jose; Peiro-Velert, Carmen; Beltran-Carrillo, Vicente J.; Tomas, Jose Manuel

2012-01-01

This study examined the relationship between socio-demographic factors, screen media time usage, and light, moderate and vigorous activities on weekdays and weekends. Cross-sectional data was collected from 323 Spanish adolescents (mean age 13.59 years) who completed an interview administered recall questionnaire. Structural equation models…

Discovery and structure activity relationships of 2-pyrazolines derived from chalcones from a pest management perspective

USDA-ARS?s Scientific Manuscript database

Synthesis of chalcones and 2-pyrazoline derivatives has been an active field of research due to the established pharmacological effects of these compounds. In this study, a series of chalcone (1a-i), 2-pyrazoline-1-carbothioamides (2a-i) and 2-pyrazoline-1-carboxamide derivatives (3a-g) were synthes...

Synthesis and structure-activity relationships of carbohydrazides and 1,3,4-oxadiazole derivatives bearing imidazolidine moiety against the yellow fever and dengue vector, Aedes aegypti

USDA-ARS?s Scientific Manuscript database

BACKGROUND: 1,3,4-oxadiazole and imidazolidine rings are important heterocyclic compounds exhibiting a variety of biological activities. In this study, novel compounds with oxadiazole and imidazolidine rings were synthesized from 3-(methylsulfonyl)-2-oxoimidazolidine-1-carbonyl chloride and screened...

Predicting Adolescents' Organized Activity Involvement: The Role of Maternal Depression History, Family Relationship Quality, and Adolescent Cognitions

ERIC Educational Resources Information Center

Bohnert, Amy M.; Martin, Nina C.; Garber, Judy

2007-01-01

Although the potential benefits of organized activity involvement during high school have been documented, little is known about what familial and individual characteristics are associated with higher levels of participation. Using structural equation modeling, this longitudinal study examined the extent to which maternal depression history (i.e.,…

Adolescents' Commitment to Developing Talent: The Role of Peers in Continuing Motivation for Sports and the Arts.

ERIC Educational Resources Information Center

Patrick, Helen; Ryan, Allison M.; Alfeld-Liro, Corinne; Fredericks, Jennifer A.; Hruda, Ludmila Z.; Eccles, Jacquelynne S.

1999-01-01

Conducted semi-structured in-depth interviews with 41 adolescents talented in sports or the arts to study the importance of peer relationships in their continued involvement in their talent activities, sex differences in attitudes, and possible differences by activity domain. Peers generally played a supportive role, although females were more…

Overhead Projector Demonstrations.

ERIC Educational Resources Information Center

Kolb, Doris, Ed.

1989-01-01

Described are three chemistry demonstrations: (1) a simple qualitative technique for taste pattern recognition in structure-activity relationships; (2) a microscale study of gaseous diffusion using bleach, HCl, ammonia, and phenolphthalein; and (3) the rotation of polarized light by stereoisomers of limonene. (MVL)

A Quantitative Analysis of the Effects of Human Activities and Climate Change on Rainfall-Runoff in Xiaoqing River Basin

NASA Astrophysics Data System (ADS)

Yang, Y.; Cao, S.; Liu, C.; Liu, Y.

2017-12-01

It is a hot topic to study the effects of human activities on the rainfall-runoff relationship and quantitatively analyze the influencing factors. According to the flexibility of Copula function to capture multivariate interdependent structure, the Copula structure between rainfall and runoff was analyzed by using the rainfall-runoff variation test method based on Archimedean Copula function to diagnose the variation of rainfall-runoff relationship. The correlation of rainfall-runoff relationship could be directly analyzed by Copula function, which could intuitively display the change of runoff in the same rainfall before and after the mutation period. The statistical method was used to simulate the underlying surface conditions before the abrupt point, and the effects of climate change and human activities on runoff changes were calculated. It can finally figure out the effects of human activities on the rainfall-runoff relationship. Taking xiaoqing river for example, the results showed that the rainfall-runoff relationship in the Xiaoqing River Basin variated in 1996 mainly due to the continuous increase of water consumption in the watershed and the change of the runoff attenuation caused by the large-scale water conservancy projects. And interannual or annual change of rainfall was not obvious; compared with the year before the variation , the runoff capacity of the basin was weakened under the same rainfall conditions after the variation ; Rainfall and runoff distribution were significantly changed and the same magnitude of rainfall and probability of runoff change were significantly different in different periods; The statistical method was used to simulate the runoff from 1996 to 2016. Compared with that from 1960 to 1995, the result showed that the contribution rate of human activities to runoff reduction was 46.8% and that of climate change was 53.2%. By relevant reference, rainfall-runoff correlation and analysis of human activities, the result was verified to be reasonable. The study can be applied to other watersheds, or used to diagnose the variation of the relationship between meteorological elements and hydrological elements so as to provide scientific basis for rational exploitation and utilization of river water resources, as well as soil and water conservation.

Structure-activity relationships of rosiglitazone for peroxisome proliferator-activated receptor gamma transrepression.

PubMed

Toyota, Yosuke; Nomura, Sayaka; Makishima, Makoto; Hashimoto, Yuichi; Ishikawa, Minoru

2017-06-15

Anti-inflammatory effects of peroxisome proliferator-activated receptor gamma (PPRAγ) ligands are thought to be largely due to PPARγ-mediated transrepression. Thus, transrepression-selective PPARγ ligands without agonistic activity or with only partial agonistic activity should exhibit anti-inflammatory properties with reduced side effects. Here, we investigated the structure-activity relationships (SARs) of PPARγ agonist rosiglitazone, focusing on transrepression activity. Alkenic analogs showed slightly more potent transrepression with reduced efficacy of transactivating agonistic activity. Removal of the alkyl group on the nitrogen atom improved selectivity for transrepression over transactivation. Among the synthesized compounds, 3l exhibited stronger transrepressional activity (IC 50 : 14μM) and weaker agonistic efficacy (11%) than rosiglitazone or pioglitazone. Copyright © 2017 Elsevier Ltd. All rights reserved.

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.

Relationship between structure and antiproliferative activity of polymethoxyflavones towards HL60 cells.

PubMed

Kawaii, Satoru; Ikuina, Tomoyasu; Hikima, Takeshi; Tokiwano, Tetsuo; Yoshizawa, Yuko

2012-12-01

As part of our continuing investigation of polymethoxyflavone (PMF) derivatives as potential anticancer substances, a series of PMF derivatives was synthesized. The synthesized compounds were evaluated for cytotoxicity against the promyelocytic leukemic HL60 cell line, and structure-activity relationship correlations were investigated along with previously isolated PMFs from the peel of king orange (Citrus nobilis). 7,3'-Dimethoxyflavone demonstrated the most potent activity among the synthetic PMFs. Consideration of correlation between the methoxylation pattern and antiproliferative activity revealed the importance of the 3'-methoxyl group and the higher degree of methoxylation on the A-ring moiety of PMFs.

Solid-phase synthesis and structure-activity relationships of novel biarylethers as melanin-concentrating hormone receptor-1 antagonists.

PubMed

Ma, Vu; Bannon, Anthony W; Baumgartner, Jamie; Hale, Clarence; Hsieh, Faye; Hulme, Christopher; Rorrer, Kirk; Salon, John; van Staden, Carlo; Tempest, Paul

2006-10-01

Melanin-concentrating hormone (MCH) is a cyclic 19 amino acid orexigenic neuropeptide. The action of MCH on feeding is thought to involve the activation of its respective G protein-coupled receptor MCH-R1. Consequently, antagonists that block MCH regulated MCH-R1 activity may provide a viable approach to the treatment of diet-induced obesity. This communication reports the discovery of a novel MCH-R1 receptor antagonist, the biarylether 7, identified through high throughput screening. The solid-phase synthesis and structure-activity relationship of related analogs is described.

A matrix-focused structure-activity and binding site flexibility study of quinolinol inhibitors of botulinum neurotoxin serotype A.

PubMed

Harrell, William A; Vieira, Rebecca C; Ensel, Susan M; Montgomery, Vicki; Guernieri, Rebecca; Eccard, Vanessa S; Campbell, Yvette; Roxas-Duncan, Virginia; Cardellina, John H; Webb, Robert P; Smith, Leonard A

2017-02-01

Our initial discovery of 8-hydroxyquinoline inhibitors of BoNT/A and separation/testing of enantiomers of one of the more active leads indicated considerable flexibility in the binding site. We designed a limited study to investigate this flexibility and probe structure-activity relationships; utilizing the Betti reaction, a 36 compound matrix of quinolinol BoNT/A LC inhibitors was developed using three 8-hydroxyquinolines, three heteroaromatic amines, and four substituted benzaldehydes. This study has revealed some of the most effective quinolinol-based BoNT/A inhibitors to date, with 7 compounds displaying IC 50 values ⩽1μM and 11 effective at ⩽2μM in an ex vivo assay. Published by Elsevier Ltd.

Investigation on Quantitative Structure Activity Relationships of a Series of Inducible Nitric Oxide.

PubMed

Sharma, Mukesh C; Sharma, S

2016-12-01

A series of 2-dihydro-4-quinazolin with potent highly selective inhibitors of inducible nitric oxide synthase activities was subjected to quantitative structure activity relationships (QSAR) analysis. Statistically significant equations with high correlation coefficient (r 2  = 0.8219) were developed. The k-nearest neighbor model has showed good cross-validated correlation coefficient and external validation values of 0.7866 and 0.7133, respectively. The selected electrostatic field descriptors the presence of blue ball around R1 and R4 in the quinazolinamine moiety showed electronegative groups favorable for nitric oxide synthase activity. The QSAR models may lead to the structural requirements of inducible nitric oxide compounds and help in the design of new compounds.

Amino acid conjugated antimicrobial drugs: Synthesis, lipophilicity- activity relationship, antibacterial and urease inhibition activity.

PubMed

Ullah, Atta; Iftikhar, Fatima; Arfan, Muhammad; Batool Kazmi, Syeda Tayyaba; Anjum, Muhammad Naveed; Haq, Ihsan-Ul; Ayaz, Muhammad; Farooq, Sadia; Rashid, Umer

2018-02-10

Present work describes the in vitro antibacterial evaluation of some new amino acid conjugated antimicrobial drugs. Structural modification was attempted on the three existing antimicrobial pharmaceuticals namely trimethoprim, metronidazole, isoniazid. Twenty one compounds from seven series of conjugates of these drugs were synthesized by coupling with some selected Boc-protected amino acids. The effect of structural features and lipophilicity on the antibacterial activity was investigated. The synthesized compounds were evaluated against five standard American type culture collection (ATCC) i.e. Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa and Salmonella typhi strains of bacteria. Our results identified a close relationship between the lipophilicity and the activity. Triazine skeleton proved beneficial for the increase in hydrophobicity and potency. Compounds with greater hydrophobicity have shown excellent activities against Gram-negative strains of bacteria than Gram-positive. 4-amino unsubstituted trimethoprim-triazine derivative 7b have shown superior activity with MIC = 3.4 μM (2 μg/mL) for S. aureus and 1.1 μM (0.66 μg/mL) for E. coli. The synthesized compounds were also evaluated for their urease inhibition study. Microbial urease from Bacillus pasteurii was chosen for this study. Triazine derivative 7a showed excellent inhibition with IC 50  = 6.23 ± 0.09 μM. Docking studies on the crystal structure of B. pasteurii urease (PDB ID 4UBP) were carried out. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

The role of Patient Health Engagement Model (PHE-model) in affecting patient activation and medication adherence: A structural equation model

PubMed Central

Graffigna, Guendalina; Bonanomi, Andrea

2017-01-01

Background Increasing bodies of scientific research today examines the factors and interventions affecting patients’ ability to self-manage and adhere to treatment. Patient activation is considered the most reliable indicator of patients’ ability to manage health autonomously. Only a few studies have tried to assess the role of psychosocial factors in promoting patient activation. A more systematic modeling of the psychosocial factors explaining the variance of patient activation is needed. Objective To test the hypothesized effect of patient activation on medication adherence; to test the the hypothesized effects of positive emotions and of the quality of the patient/doctor relationship on patient activation; and to test the hypothesized mediating effect of Patient Health Engagement (PHE-model) in this pathway. Material and methods This cross-sectional study involved 352 Italian-speaking adult chronic patients. The survey included measures of i) patient activation (Patient Activation Measure 13 –short form); ii) Patient Health Engagement model (Patient Health Engagement Scale); iii) patient adherence (4 item-Morinsky Medication Adherence Scale); iv) the quality of the patients’ emotional feelings (Manikin Self Assessment Scale); v) the quality of the patient/doctor relationship (Health Care Climate Questionnaire). Structural equation modeling was used to test the hypotheses proposed. Results According to the theoretical model we hypothesized, research results confirmed that patients’ activation significantly affects their reported medication adherence. Moreover, psychosocial factors, such as the patients’ quality of the emotional feelings and the quality of the patient/doctor relationship were demonstrated to be factors affecting the level of patient activation. Finally, the mediation effect of the Patient Health Engagement model was confirmed by the analysis. Conclusions Consistently with the results of previous studies, these findings demonstrate that the Patient Health Engagement Model is a critical factor in enhancing the quality of care. The Patient Health Engagement Model might acts as a mechanism to increase patient activation and adherence. PMID:28654686

The role of Patient Health Engagement Model (PHE-model) in affecting patient activation and medication adherence: A structural equation model.

PubMed

Graffigna, Guendalina; Barello, Serena; Bonanomi, Andrea

2017-01-01

Increasing bodies of scientific research today examines the factors and interventions affecting patients' ability to self-manage and adhere to treatment. Patient activation is considered the most reliable indicator of patients' ability to manage health autonomously. Only a few studies have tried to assess the role of psychosocial factors in promoting patient activation. A more systematic modeling of the psychosocial factors explaining the variance of patient activation is needed. To test the hypothesized effect of patient activation on medication adherence; to test the the hypothesized effects of positive emotions and of the quality of the patient/doctor relationship on patient activation; and to test the hypothesized mediating effect of Patient Health Engagement (PHE-model) in this pathway. This cross-sectional study involved 352 Italian-speaking adult chronic patients. The survey included measures of i) patient activation (Patient Activation Measure 13 -short form); ii) Patient Health Engagement model (Patient Health Engagement Scale); iii) patient adherence (4 item-Morinsky Medication Adherence Scale); iv) the quality of the patients' emotional feelings (Manikin Self Assessment Scale); v) the quality of the patient/doctor relationship (Health Care Climate Questionnaire). Structural equation modeling was used to test the hypotheses proposed. According to the theoretical model we hypothesized, research results confirmed that patients' activation significantly affects their reported medication adherence. Moreover, psychosocial factors, such as the patients' quality of the emotional feelings and the quality of the patient/doctor relationship were demonstrated to be factors affecting the level of patient activation. Finally, the mediation effect of the Patient Health Engagement model was confirmed by the analysis. Consistently with the results of previous studies, these findings demonstrate that the Patient Health Engagement Model is a critical factor in enhancing the quality of care. The Patient Health Engagement Model might acts as a mechanism to increase patient activation and adherence.

Discovery of a Manduca sexta Allatotropin Antagonist from a Manduca sexta Allatotropin Receptor Homology Model.

PubMed

Kai, Zhen-Peng; Zhu, Jing-Jing; Deng, Xi-Le; Yang, Xin-Ling; Chen, Shan-Shan

2018-04-03

Insect G protein coupled receptors (GPCRs) have important roles in modulating biology, physiology and behavior. They have been identified as candidate targets for next-generation insecticides, yet these targets have been relatively poorly exploited for insect control. In this study, we present a pipeline of novel Manduca sexta allatotropin (Manse-AT) antagonist discovery with homology modeling, docking, molecular dynamics simulation and structure-activity relationship. A series of truncated and alanine-replacement analogs of Manse-AT were assayed for the stimulation of juvenile hormone biosynthesis. The minimum sequence required to retain potent biological activity is the C -terminal amidated octapeptide Manse-AT (6-13). We identified three residues essential for bioactivity (Thr⁴, Arg6 and Phe⁸) by assaying alanine-replacement analogs of Manse-AT (6-13). Alanine replacement of other residues resulted in reduced potency but bioactivity was retained. The 3D structure of the receptor (Manse-ATR) was built and the binding pocket was identified. The binding affinities of all the analogs were estimated by calculating the free energy of binding. The calculated binding affinities corresponded to the biological activities of the analogs, which supporting our localization of the binding pocket. Then, based on the docking and molecular dynamics studies of Manse-AT (10-13), we described it can act as a potent Manse-AT antagonist. The antagonistic effect on JH biosynthesis of Manse-AT (10-13) validated our hypothesis. The IC 50 value of antagonist Manse-AT (10-13) is 0.9 nM. The structure-activity relationship of antagonist Manse-AT (10-13) was also studied for the further purpose of investigating theoretically the structure factors influencing activity. These data will be useful for the design of new Manse-AT agonist and antagonist as potential pest control agents.

Effect of crown class and habitat type on climate-growth relationships of ponderosa pine and Douglas-fir

Treesearch

Gunnar C. Carnwath; David W. Peterson; Cara R. Nelson

2012-01-01

There is increasing interest in actively managing forests to increase their resilience to climate-related changes. Although forest managers rely heavily on the use of silvicultural treatments that manipulate stand structure and stand dynamics to modify responses to climate change, few studies have directly assessed the effects of stand structure or canopy position on...

Decoding the Structure of Abuse Potential for New Psychoactive Substances: Structure—Activity Relationships for Abuse-Related Effects of 4-Substituted Methcathinone Analogs

PubMed Central

Banks, Matthew L.

2017-01-01

Many cathinone analogs act as substrates or inhibitors at dopamine, norepinephrine, and serotonin transporters (DAT, NET, SERT, respectively). Drug selectivity at DAT vs. SERT is a key determinant of abuse potential for monoamine transporter substrates and inhibitors, such that potency at DAT > SERT is associated with high abuse potential, whereas potency at DAT < SERT is associated with low abuse potential. Quantitative structure—activity relationship (QSAR) studies with a series of 4-substituted methcathinone analogs identified volume of the 4-position substituent on the methcathinone phenyl ring as one structural determinant of both DAT vs. SERT selectivity and abuse-related behavioral effects in an intracranial self-stimulation procedure in rats. Subsequent modeling studies implicated specific amino acids in DAT and SERT that might interact with 4-substituent volume to determine effects produced by this series of cathinone analogs. These studies illustrate use of QSAR analysis to investigate pharmacology of cathinones and function of monoamine transporters. PMID:27696217

Synthesis and Structure-activity Relationship Studies of O-Biphenyl-3-yl Carbamates as Peripherally Restricted Fatty Acid Amide Hydrolase Inhibitors

PubMed Central

Moreno-Sanz, Guillermo; Duranti, Andrea; Melzig, Laurin; Fiorelli, Claudio; Ruda, Gian Filippo; Colombano, Giampiero; Mestichelli, Paola; Sanchini, Silvano; Tontini, Andrea; Mor, Marco; Bandiera, Tiziano; Scarpelli, Rita; Tarzia, Giorgio; Piomelli, Daniele

2014-01-01

The peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor URB937 (3, cyclohexylcarbamic acid 3’-carbamoyl-6-hydroxybiphenyl-3-yl ester) is extruded from the brain and spinal cord by the Abcg2 efflux transporter. Despite its inability to enter the central nervous system (CNS), 3 exerts profound antinociceptive effects in mice and rats, which result from the inhibition of FAAH in peripheral tissues and the consequent enhancement of anandamide signaling at CB1 cannabinoid receptors localized on sensory nerve endings. In the present study, we examined the structure-activity relationships (SAR) for the biphenyl region of compound 3, focusing on the carbamoyl and hydroxyl groups in the distal and proximal phenyl rings. Our SAR studies generated a new series of peripherally restricted FAAH inhibitors and identified compound 35 (cyclohexylcarbamic acid 3’-carbamoyl-5-hydroxybiphenyl-3-yl ester) as the most potent brain-impermeant FAAH inhibitor disclosed to date. PMID:23822179

pH-Dependent Solution Structure and Activity of a Reduced Form of the Host-Defense Peptide Myticin C (Myt C) from the Mussel Mytilus galloprovincialis

PubMed Central

Martinez-Lopez, Alicia; Encinar, Jose Antonio; Medina-Gali, Regla Maria; Balseiro, Pablo; Garcia-Valtanen, Pablo; Figueras, Antonio; Novoa, Beatriz; Estepa, Amparo

2013-01-01

Myticin C (Myt C) is a highly variable host-defense peptide (HDP) associated to the immune response in the mediterranean mussel (Mytilus galloprovincialis), which has shown to be active across species due to its strong antiviral activity against a fish rhabdovirus found in fish cells overexpressing this HDP. However, the potential antimicrobial properties of any synthetic analogue of Myt C has not yet been analysed. Thus, in this work we have synthesised the sequence of the mature peptide of Myt C variant c and analysed the structure activity relationships of its reduced (non-oxidized) form (red-MytCc). In contrast to results previously reported for oxidized isoforms of mussel myticins, red-MytCc was not active against bacteria at physiological pH and showed a moderate antiviral activity against the viral haemorrhagic septicaemia (VHS) rhabdovirus. However, its chemotactic properties remained active. Structure/function studies in neutral and acid environments by means of infrared spectroscopy indicated that the structure of red-MytCc is pH dependent, with acid media increasing its alpha-helical content. Furthermore, red-MytCc was able to efficiently aggregate artificial phospholipid membranes at low pH, as well as to inhibit the Escherichia coli growth, suggesting that this activity is attributable to its more structured form in an acidic environment. All together, these results highlight the dynamic and environmentally sensitive behavior of red-Myt C in solution, and provide important insights into Myt C structure/activity relationships and the requirements to exert its antimicrobial/immunomodulatory activities. On the other hand, the pH-dependent direct antimicrobial activity of Myt C suggests that this HDP may be a suitable template for the development of antimicrobial agents that would function selectively in specific pH environments, which are sorely needed in this “antibiotic-resistance era”. PMID:23880927

Structure-Activity and Lipophilicity Relationships of Selected Antibacterial Natural Flavones and Flavanones of Chilean Flora.

PubMed

Echeverría, Javier; Opazo, Julia; Mendoza, Leonora; Urzúa, Alejandro; Wilkens, Marcela

2017-04-10

In this study, we tested eight naturally-occurring flavonoids-three flavanones and five flavones-for their possible antibacterial properties against four Gram-positive and four Gram-negative bacteria. Flavonoids are known for their antimicrobial properties, and due their structural diversity; these plant-derived compounds are a good model to study potential novel antibacterial mechanisms. The lipophilicity and the interaction of antibacterial compounds with the cell membrane define the success or failure to access its target. Therefore, through the determination of partition coefficients in a non-polar/aqueous phase, lipophilicity estimation and the quantification of the antibacterial activity of different flavonoids, flavanones, and flavones, a relationship between these parameters was assessed. Active flavonoids presented diffusion coefficients between 9.4 × 10 -10 and 12.3 × 10 -10 m²/s and lipophilicity range between 2.0 to 3.3. Active flavonoids against Gram-negative bacteria showed a narrower range of lipophilicity values, compared to active flavonoids against Gram-positive bacteria, which showed a wide range of lipophilicity and cell lysis. Galangin was the most active flavonoid, whose structural features are the presence of two hydroxyl groups located strategically on ring A and the absence of polar groups on ring B. Methylation of one hydroxyl group decreases the activity in 3- O -methylgalangin, and methylation of both hydroxyl groups caused inactivation, as shown for 3,7- O -dimethylgalangin. In conclusion, the amphipathic features of flavonoids play a crucial role in the antibacterial activity. In these compounds, hydrophilic and hydrophobic moieties must be present and could be predicted by lipophilicity analysis.

Computer-Aided Drug Design Methods.

PubMed

Yu, Wenbo; MacKerell, Alexander D

2017-01-01

Computational approaches are useful tools to interpret and guide experiments to expedite the antibiotic drug design process. Structure-based drug design (SBDD) and ligand-based drug design (LBDD) are the two general types of computer-aided drug design (CADD) approaches in existence. SBDD methods analyze macromolecular target 3-dimensional structural information, typically of proteins or RNA, to identify key sites and interactions that are important for their respective biological functions. Such information can then be utilized to design antibiotic drugs that can compete with essential interactions involving the target and thus interrupt the biological pathways essential for survival of the microorganism(s). LBDD methods focus on known antibiotic ligands for a target to establish a relationship between their physiochemical properties and antibiotic activities, referred to as a structure-activity relationship (SAR), information that can be used for optimization of known drugs or guide the design of new drugs with improved activity. In this chapter, standard CADD protocols for both SBDD and LBDD will be presented with a special focus on methodologies and targets routinely studied in our laboratory for antibiotic drug discoveries.

Structure-activity relationship of S-trityl-L-cysteine analogues as inhibitors of the human mitotic kinesin Eg5.

PubMed

Debonis, Salvatore; Skoufias, Dimitrios A; Indorato, Rose-Laure; Liger, François; Marquet, Bernard; Laggner, Christian; Joseph, Benoît; Kozielski, Frank

2008-03-13

The human kinesin Eg5 is a potential drug target for cancer chemotherapy. Eg5 specific inhibitors cause cells to block in mitosis with a characteristic monoastral spindle phenotype. Prolonged metaphase block eventually leads to apoptotic cell death. S-trityl-L-cysteine (STLC) is a tight-binding inhibitor of Eg5 that prevents mitotic progression. It has proven antitumor activity as shown in the NCI 60 tumor cell line screen. It is of considerable interest to define the minimum chemical structure that is essential for Eg5 inhibition and to develop more potent STLC analogues. An initial structure-activity relationship study on a series of STLC analogues reveals the minimal skeleton necessary for Eg5 inhibition as well as indications of how to obtain more potent analogues. The most effective compounds investigated with substitutions at the para-position of one phenyl ring have an estimated K i (app) of 100 nM in vitro and induce mitotic arrest with an EC 50 of 200 nM.

Spatial relationships between crustal structures and mantle seismicity in the Vrancea Seismogenic Zone of Romania: Implications for geodynamic evolution

NASA Astrophysics Data System (ADS)

Enciu, Dana-Mihaela

Integration of active and passive-source seismic data is employed to study the relationships between crustal structures and seismicity in the SE Carpathian foreland of Romania, and the connection with the Vrancea Seismogenic Zone. Relocated crustal epicenters and focal mechanisms are correlated with industry seismic profiles Comanesti, Ramnicu Sarat, Braila and Buzau, the reprocessed DACIA PLAN profile and the DRACULA (Deep Reflection Acquisition Constraining Unusual Lithospheric Activity) II and III profiles in order to understand the link between neo-tectonic foreland deformation and Vrancea mantle seismicity. Projection of crustal foreland hypocenters onto deep seismic profiles identified active crustal faults suggesting a mechanical coupling between sedimentary, crustal and upper mantle structures on the Trotus, Sinaia and newly observed Ialomita Faults. Seismic reflection imaging revealed the absence of west dipping reflectors in the crust and an east dipping to horizontal Moho in the proximity of the Vrancea area. These findings argue against both 'subduction-in-place' and 'slab break-off' as viable mechanisms for generating Vrancea mantle seismicity.

Structure-activity relationships of insect defensins

NASA Astrophysics Data System (ADS)

Koehbach, Johannes

2017-07-01

Insects make up the largest and most diverse group of organisms on earth with several million species to exist in total. Considering the sheer number of insect species and the vast variety of ways they interact with their environment through chemistry, it is clear that they have significant potential as a source of new lead molecules. They have adapted to a range of ecological habitats and exhibit a symbiotic lifestyle with various microbes such as bacteria and fungi. Accordingly, numerous antimicrobial compounds have been identified including for example defensin peptides. Insect defensins were found to have broad-spectrum activity against various gram-positive/negative bacteria as well as fungi. They exhibit a unique structural topology involving the complex arrangement of three disulfide bonds as well as an alpha helix and beta sheets, which is known as cysteine-stabilized αβ motif. Their stability and amenability to peptide engineering make them promising candidates for the development of novel antibiotics lead molecules. This review highlights the current knowledge regarding the structure-activity relationships of insect defensin peptides and provides basis for future studies focusing on the rational design of novel cysteine-rich antimicrobial peptides.

Experimental and QSAR study on the surface activities of alkyl imidazoline surfactants

NASA Astrophysics Data System (ADS)

Kong, Xiangjun; Qian, Chengduo; Fan, Weiyu; Liang, Zupei

2018-03-01

15 alkyl imidazoline surfactants with different structures were synthesized and their critical micelle concentration (CMC) and surface tension under the CMC (σcmc) in aqueous solution were measured at 298 K. 54 kinds of molecular structure descriptors were selected as independent variables and the quantitative structure-activity relationship (QSAR) between surface activities of alkyl imidazoline and molecular structure were built through the genetic function approximation (GFA) method. Experimental results showed that the maximum surface excess of alkyl imidazoline molecules at the gas-liquid interface increased and the area occupied by each surfactant molecule and the free energies of micellization ΔGm decreased with increasing carbon number (NC) of the hydrophobic chain or decreasing hydrophilicity of counterions, which resulted in a CMC and σcmc decrease, while the log CMC and NC had a linear relationship and a negative correlation. The GFA-QSAR model, which was generated by a training set composed of 13 kinds of alkyl imidazoline though GFA method regression analysis, was highly correlated with predicted values and experimental values of the CMC. The correlation coefficient R was 0.9991, which means high prediction accuracy. The prediction error of 2 kinds of alkyl imidazoline CMCs in the Validation Set that quantitatively analyzed the influence of the alkyl imidazoline molecular structure on the CMC was less than 4%.

Studies of the structure-activity relationships of peptides and proteins involved in growth and development based on their three-dimensional structures.

PubMed

Nagata, Koji

2010-01-01

Peptides and proteins with similar amino acid sequences can have different biological functions. Knowledge of their three-dimensional molecular structures is critically important in identifying their functional determinants. In this review, I describe the results of our and other groups' structure-based functional characterization of insect insulin-like peptides, a crustacean hyperglycemic hormone-family peptide, a mammalian epidermal growth factor-family protein, and an intracellular signaling domain that recognizes proline-rich sequence.

Dihydro-β-agarofuran sesquiterpenes from celastraceae species as anti-tumour-promoting agents: Structure-activity relationship.

PubMed

Núñez, Marvin J; Jiménez, Ignacio A; Mendoza, Cristina R; Chavez-Sifontes, Marvin; Martinez, Morena L; Ichiishi, Eiichiro; Tokuda, Ryo; Tokuda, Harukuni; Bazzocchi, Isabel L

2016-03-23

Inhibition of tumour promotion in multistage chemical carcinogenesis is considered a promising strategy for cancer chemoprevention. In an ongoing investigation of bioactive secondary metabolites from Celastraceae species, five new dihydro-β-agarofuran sesquiterpenes (1-5), named Chiapens A-E, and seventeen known ones, were isolated from Maytenus chiapensis. Their structures were elucidated by extensive NMR spectroscopic and mass spectrometric techniques, and their absolute configurations were determined by circular dichroism studies, chemical correlations and biogenic means. The isolated compounds, along with twenty known sesquiterpenes, previously isolated from Zinowiewia costaricensis, have been tested for their inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorpol-13-acetate (TPA). Thirty three compounds from this series showed stronger effects than that of β-carotene, the reference inhibitor. The structure-activity relationship (SAR) analysis revealed that the type of substituent, in particular at the C-1 position of the sesquiterpene scaffold, was able to modulate the anti-tumour promoting activity. Compounds 3, 6, and 33 showed significant effects in an in vivo two-stage mouse-skin carcinogenesis model. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

In vitro-in vivo activity relationship of substituted benzimidazole cell division inhibitors with activity against Mycobacteria tuberculosis

PubMed Central

Knudson, Susan E.; Kumar, Kunal; Awasthi, Divya; Ojima, Iwao; Slayden, Richard A.

2014-01-01

Structure based drug design was used to develop a compound library of novel 2,5,6- and 2,5,7-trisubstituted benzimidazoles. Three structural analogs, SB-P1G10, SB-P8B2 and SB-P3G2 were selected from this library based on previous studies for advanced study. In vitro studies revealed that SB-P8B2 and SB-P3G2 had sigmoidal kill-curves while in contrast SB-P1G10 showed a narrow zonal susceptibility. The in vitro studies also demonstrated that exposure to SB-P8B2 or SB-P3G2 was bactericidal, while SB-P1G10 treatment never resulted in complete killing. The dose curves for the three compounds against clinical isolates were comparable to their respective dose curves in the laboratory strain of M. tuberculosis. SB-P8B2 and SB-P3G2 exhibited antibacterial activity against non-replicating bacilli under low oxygen conditions. SB-P3G2 and SB-P1G10 were assessed in acute short-term animal models of tuberculosis, which showed that SB-P3G2 treatment demonstrated activity against M. tuberculosis. Together, these studies reveal an in vitro- in vivo relationship of the 2,5,6-trisubstituted benzimidazoles that serves as a criterion for advancing this class of cell division inhibitors into more resource intensive in vivo efficacy models such as the long-term murine model of tuberculosis and Pre-IND PK/PD studies. Specifically, these studies are the first demonstration of efficacy and an in vitro–in vivo activity relationship for 2,5,6-trisubstituted benzimidazoles. The in vivo activity presented in this manuscript substantiates this class of cell division inhibitors as having potency and efficacy against M. tuberculosis. PMID:24746463

Non-anticoagulant effects of low molecular weight heparins in inflammatory disorders: A review.

PubMed

Yan, Yishu; Ji, Yang; Su, Nan; Mei, Xiang; Wang, Yi; Du, Shanshan; Zhu, Wenming; Zhang, Chong; Lu, Yuan; Xing, Xin-Hui

2017-03-15

Low molecular weight heparins (LMWHs) are produced by chemical or enzymatic depolymerization of unfractionated heparin (UFH). Besides their well-known anticoagulant effects, LMWHs have also been reported to exhibit numerous anti-inflammatory properties. Previous studies have, however, shown that different production processes result in unique structural characteristics of LMWHs. The structural variations may help explain the different therapeutic spectrums in disease treatment for non-anticoagulant effects. In the present review, we summarize major advances in understanding and exploiting the anti-inflammatory disorder activities of LMWHs, based on mechanistic studies, preclinical experiments and clinical trials. We highlight differences in these activities of commercially available LMWHs produced using different manufacturing processes. We stress the importance of structure-activity relationship (SAR) studies on the non-anticoagulant effects of LMWHs and discuss strategies for exploring new clinical indications. Copyright © 2016 Elsevier Ltd. All rights reserved.

QSAR, docking and ADMET studies of artemisinin derivatives for antimalarial activity targeting plasmepsin II, a hemoglobin-degrading enzyme from P. falciparum.

PubMed

Qidwai, Tabish; Yadav, Dharmendra K; Khan, Feroz; Dhawan, Sangeeta; Bhakuni, R S

2012-01-01

This work presents the development of quantitative structure activity relationship (QSAR) model to predict the antimalarial activity of artemisinin derivatives. The structures of the molecules are represented by chemical descriptors that encode topological, geometric, and electronic structure features. Screening through QSAR model suggested that compounds A24, A24a, A53, A54, A62 and A64 possess significant antimalarial activity. Linear model is developed by the multiple linear regression method to link structures to their reported antimalarial activity. The correlation in terms of regression coefficient (r(2)) was 0.90 and prediction accuracy of model in terms of cross validation regression coefficient (rCV(2)) was 0.82. This study indicates that chemical properties viz., atom count (all atoms), connectivity index (order 1, standard), ring count (all rings), shape index (basic kappa, order 2), and solvent accessibility surface area are well correlated with antimalarial activity. The docking study showed high binding affinity of predicted active compounds against antimalarial target Plasmepsins (Plm-II). Further studies for oral bioavailability, ADMET and toxicity risk assessment suggest that compound A24, A24a, A53, A54, A62 and A64 exhibits marked antimalarial activity comparable to standard antimalarial drugs. Later one of the predicted active compound A64 was chemically synthesized, structure elucidated by NMR and in vivo tested in multidrug resistant strain of Plasmodium yoelii nigeriensis infected mice. The experimental results obtained agreed well with the predicted values.

Structural, morphological, and optical study of titania-based nanopowders suitable for photocatalytic applications

NASA Astrophysics Data System (ADS)

Šćepanović, M.; Grujić-Brojčin, M.; Abramović, B.; Golubović, A.

2017-01-01

Systematic investigation of the relationship between structural, morphological, optical and photocatalytic properties of the titania-based nanopowders is presented. A series of pure and doped titania catalysts with various (anatase and brookite) phase compositions have been prepared by sol-gel or hydrothermal route. The crystal structure and composition of the synthesized samples have been extensively characterised by XRD and Raman scattering measurements. The nanopowder morphology has been studied using microscopic methods (SEM, AFM, and STM), whereas the porous structure has been revealed by the analysis of nitrogen sorption data. The optical and electronic properties have been studied by spectroscopic ellipsometry. All investigated properties have been correlated to photocatalytic activity, tested in degradation of the pharmaceutically active substances (such as metoprolol and alprazolam) induced by UVA or visible radiation. Based on this correlation, the physical properties which contribute most to the increase in photocatalytic activity of synthesized nanopowders have been determined, in order to optimize the synthesis conditions which could lead to the maximal efficiency in degradation of particular pollutant.

Calpain chronicle--an enzyme family under multidisciplinary characterization.

PubMed

Sorimachi, Hiroyuki; Hata, Shoji; Ono, Yasuko

2011-01-01

Calpain is an intracellular Ca2+-dependent cysteine protease (EC 3.4.22.17; Clan CA, family C02) discovered in 1964. It was also called CANP (Ca2+-activated neutral protease) as well as CASF, CDP, KAF, etc. until 1990. Calpains are found in almost all eukaryotes and a few bacteria, but not in archaebacteria. Calpains have a limited proteolytic activity, and function to transform or modulate their substrates' structures and activities; they are therefore called, "modulator proteases." In the human genome, 15 genes--CAPN1, CAPN2, etc.--encode a calpain-like protease domain. Their products are calpain homologs with divergent structures and various combinations of functional domains, including Ca2+-binding and microtubule-interaction domains. Genetic studies have linked calpain deficiencies to a variety of defects in many different organisms, including lethality, muscular dystrophies, gastropathy, and diabetes. This review of the study of calpains focuses especially on recent findings about their structure-function relationships. These discoveries have been greatly aided by the development of 3D structural studies and genetic models.

4-Aminoquinolines Active against Chloroquine-Resistant Plasmodium falciparum: Basis of Antiparasite Activity and Quantitative Structure-Activity Relationship Analyses▿

PubMed Central

Hocart, Simon J.; Liu, Huayin; Deng, Haiyan; De, Dibyendu; Krogstad, Frances M.; Krogstad, Donald J.

2011-01-01

Chloroquine (CQ) is a safe and economical 4-aminoquinoline (AQ) antimalarial. However, its value has been severely compromised by the increasing prevalence of CQ resistance. This study examined 108 AQs, including 68 newly synthesized compounds. Of these 108 AQs, 32 (30%) were active only against CQ-susceptible Plasmodium falciparum strains and 59 (55%) were active against both CQ-susceptible and CQ-resistant P. falciparum strains (50% inhibitory concentrations [IC50s], ≤25 nM). All AQs active against both CQ-susceptible and CQ-resistant P. falciparum strains shared four structural features: (i) an AQ ring without alkyl substitution, (ii) a halogen at position 7 (Cl, Br, or I but not F), (iii) a protonatable nitrogen at position 1, and (iv) a second protonatable nitrogen at the end of the side chain distal from the point of attachment to the AQ ring via the nitrogen at position 4. For activity against CQ-resistant parasites, side chain lengths of ≤3 or ≥10 carbons were necessary but not sufficient; they were identified as essential factors by visual comparison of 2-dimensional (2-D) structures in relation to the antiparasite activities of the AQs and were confirmed by computer-based 3-D comparisons and differential contour plots of activity against P. falciparum. The advantage of the method reported here (refinement of quantitative structure-activity relationship [QSAR] descriptors by random assignment of compounds to multiple training and test sets) is that it retains QSAR descriptors according to their abilities to predict the activities of unknown test compounds rather than according to how well they fit the activities of the compounds in the training sets. PMID:21383099

Antimicrobial peptides: a review of how peptide structure impacts antimicrobial activity

NASA Astrophysics Data System (ADS)

Soares, Jason W.; Mello, Charlene M.

2004-03-01

Antimicrobial peptides (AMPs) have been discovered in insects, mammals, reptiles, and plants to protect against microbial infection. Many of these peptides have been isolated and studied exhaustively to decipher the molecular mechanisms that impart protection against infectious bacteria, fungi, and viruses. Unfortunately, the molecular mechanisms are still being debated within the scientific community but valuable clues have been obtained through structure/function relationship studies1. Biophysical studies have revealed that cecropins, isolated from insects and pigs, exhibit random structure in solution but undergo a conformational change to an amphipathic α-helix upon interaction with a membrane surface2. The lack of secondary structure in solution results in an extremely durable peptide able to survive exposure to high temperatures, organic solvents and incorporation into fibers and films without compromising antibacterial activity. Studies to better understand the antimicrobial action of cecropins and other AMPs have provided insight into the importance of peptide sequence and structure in antimicrobial activities. Therefore, enhancing our knowledge of how peptide structure imparts function may result in customized peptide sequences tailored for specific applications such as targeted cell delivery systems, novel antibiotics and food preservation additives. This review will summarize the current state of knowledge with respect to cell binding and antimicrobial activity of AMPs focusing primarily upon cecropins.

MS/MS fragmentation-guided search of TMG-chitooligomycins and their structure-activity relationship in specific β-N-acetylglucosaminidase inhibition.

PubMed

Usuki, Hirokazu; Yamamoto, Yukihiro; Kumagai, Yuya; Nitoda, Teruhiko; Kanzaki, Hiroshi; Hatanaka, Tadashi

2011-04-21

The reducing tetrasaccharide TMG-chitotriomycin (1) is an inhibitor of β-N-acetylglucosaminidase (GlcNAcase), produced by the actinomycete Streptomyces anulatus NBRC13369. The inhibitor shows a unique inhibitory spectrum, that is, selectivity toward enzymes from chitin-containing organisms such as insects and fungi. Nevertheless, its structure-selectivity relationship remains to be clarified. In this study, we conducted a structure-guided search of analogues of 1 in order to obtain diverse N,N,N-trimethylglucosaminium (TMG)-containing chitooligosaccharides. In this approach, the specific fragmentation profile of 1 on ESI-MS/MS analysis was used for the selective detection of desired compounds. As a result, two new analogues, named TMG-chitomonomycin (3) and TMG-chitobiomycin (2), were obtained from a culture filtrate of 1-producing Streptomyces. Their enzyme-inhibiting activity revealed that the potency and selectivity depended on the degree of polymerization of the reducing end GlcNAc units. Furthermore, a computational modeling study inspired the inhibitory mechanism of TMG-related compounds as a mimic of the substrate in the Michaelis complex of the GH20 enzyme. This study is an example of the successful application of a MS/MS experiment for structure-guided isolation of natural products.

The interaction of flavonoid-lysozyme and the relationship between molecular structure of flavonoids and their binding activity to lysozyme.

PubMed

Yang, Ran; Yu, Lanlan; Zeng, Huajin; Liang, Ruiling; Chen, Xiaolan; Qu, Lingbo

2012-11-01

In this work, the interactions of twelve structurally different flavonoids with Lysozyme (Lys) were studied by fluorescence quenching method. The interaction mechanism and binding properties were investigated. It was found that the binding capacities of flavonoids to Lys were highly depend on the number and position of hydrogen, the kind and position of glycosyl. To explore the selectivity of the bindings of flavonoids with Lys, the structure descriptors of the flavonoids were calculated under QSAR software package of Cerius2, the quantitative relationship between the structures of flavonoids and their binding activities to Lys (QSAR) was performed through genetic function approximation (GFA) regression analysis. The QSAR regression equation was K(A) = 37850.460 + 1630.01Dipole +3038.330HD-171.795MR. (r = 0.858, r(CV)(2) = 0.444, F((11,3)) = 7.48), where K(A) is binding constants, Dipole, HD and MR was dipole moment, number of hydrogen-bond donor and molecular refractivity, respectively. The obtained results make us understand better how the molecular structures influencing their binding to protein which may open up new avenues for the design of the most suitable flavonoids derivatives with structure variants.

Social capital calculations in economic systems: Experimental study

NASA Astrophysics Data System (ADS)

Chepurov, E. G.; Berg, D. B.; Zvereva, O. M.; Nazarova, Yu. Yu.; Chekmarev, I. V.

2017-11-01

The paper describes the social capital study for a system where actors are engaged in an economic activity. The focus is on the analysis of communications structural parameters (transactions) between the actors. Comparison between transaction network graph structure and the structure of a random Bernoulli graph of the same dimension and density allows revealing specific structural features of the economic system under study. Structural analysis is based on SNA-methodology (SNA - Social Network Analysis). It is shown that structural parameter values of the graph formed by agent relationship links may well characterize different aspects of the social capital structure. The research advocates that it is useful to distinguish the difference between each agent social capital and the whole system social capital.

Regulation of Complement and Contact System Activation via C1 Inhibitor Potentiation and Factor XIIa Activity Modulation by Sulfated Glycans – Structure-Activity Relationships

PubMed Central

Schoenfeld, Ann-Kathrin; Lahrsen, Eric; Alban, Susanne

2016-01-01

The serpin C1 inhibitor (C1-INH) is the only regulator of classical complement activation as well as the major regulator of the contact system. Its importance is demonstrated by hereditary angioedema (HAE), a severe disease with potentially life-threatening attacks due to deficiency or dysfunction of C1-INH. C1-INH replacement is the therapy of choice in HAE. In addition, C1-INH showed to have beneficial effects in other diseases characterized by inappropriate complement and contact system activation. Due to some limitations of its clinical application, there is a need for improving the efficacy of therapeutically applied C1-INH or to enhance the activity of endogenous C1-INH. Given the known potentiating effect of heparin on C1-INH, sulfated glycans (SG) may be such candidates. The aim of this study was to characterize suitable SG by evaluating structure-activity relationships. For this, more than 40 structurally distinct SG were examined for their effects on C1-INH, C1s and FXIIa. The SG turned out to potentiate the C1s inhibition by C1-INH without any direct influence on C1s. Their potentiating activity proved to depend on their degree of sulfation, molecular mass as well as glycan structure. In contrast, the SG had no effect on the FXIIa inhibition by C1-INH, but structure-dependently modulated the activity of FXIIa. Among the tested SG, β-1,3-glucan sulfates with a Mr ≤ 10 000 were identified as most promising lead candidates for the development of a glycan-based C1-INH amplifier. In conclusion, the obtained information on structural characteristics of SG favoring C1-INH potentiation represent an useful elementary basis for the development of compounds improving the potency of C1-INH in diseases and clinical situations characterized by inappropriate activation of complement and contact system. PMID:27783665

Structure-In Vitro Activity Relationships of Pentamidine Analogues and Dication-Substituted Bis-Benzimidazoles as New Antifungal Agents

PubMed Central

Del Poeta, Maurizio; Schell, Wiley A.; Dykstra, Christine C.; Jones, Susan; Tidwell, Richard R.; Czarny, Agnieszka; Bajic, Miroslav; Bajic, Marina; Kumar, Arvind; Boykin, David; Perfect, John R.

1998-01-01

Twenty analogues of pentamidine, 7 primary metabolites of pentamidine, and 30 dicationic substituted bis-benzimidazoles were screened for their inhibitory and fungicidal activities against Candida albicans and Cryptococcus neoformans. A majority of the compounds had MICs at which 80% of the strains were inhibited (MIC80s) comparable to those of amphotericin B and fluconazole. Unlike fluconazole, many of these compounds were found to have potent fungicidal activity. The most potent compound against C. albicans had an MIC80 of ≤0.09 μg/ml, and the most potent compound against C. neoformans had an MIC80 of 0.19 μg/ml. Selected compounds were also found to be active against Aspergillus fumigatus, Fusarium solani, Candida species other than C. albicans, and fluconazole-resistant strains of C. albicans and C. neoformans. It is clear from the data presented here that further studies on the structure-activity relationships, mechanisms of action and toxicities, and in vivo efficacies of these compounds are warranted to determine their clinical potential. PMID:9756747

Design, synthesis, and evaluation of a novel series of alpha-substituted phenylpropanoic acid derivatives as human peroxisome proliferator-activated receptor (PPAR) alpha/delta dual agonists for the treatment of metabolic syndrome.

PubMed

Kasuga, Jun-ichi; Yamasaki, Daisuke; Araya, Yoko; Nakagawa, Aya; Makishima, Makoto; Doi, Takefumi; Hashimoto, Yuichi; Miyachi, Hiroyuki

2006-12-15

A series of alpha-alkyl-substituted phenylpropanoic acids was prepared as dual agonists of peroxisome proliferator-activated receptors alpha and delta (PPARalpha/delta). Structure-activity relationship studies indicated that the shape of the linking group and the shape of the substituent at the distal benzene ring play key roles in determining the potency and the selectivity of PPAR subtype transactivation. Structure-activity relationships among the amide series (10) and the reversed amide series (13) are similar, but not identical, especially in the case of the compounds bearing a bulky hydrophobic substituent at the distal benzene ring, indicating that the hydrophobic tail part of the molecules in these two series binds at somewhat different positions in the large binding pocket of PPAR. alpha-Alkyl-substituted phenylpropanoic acids of (S)-configuration were identified as potent human PPARalpha/delta dual agonists. Representative compounds exhibited marked nuclear receptor selectivity for PPARalpha and PPARdelta. Subtype-selective PPAR activation was also examined by analysis of the mRNA expression of PPAR-regulated genes.

Lipophilicity-related inhibition of blood platelet aggregation by nipecotic acid anilides.

PubMed

De Marco, Agostino; De Candia, Modesto; Carotti, Andrea; Cellamare, Saverio; De Candia, Erica; Altomare, Cosimo

2004-06-01

Using N-[4-(hexyloxy)phenyl]piperidine-3-carboxamide (17c) as a structural lead, a number of isomers, derivatives, and ring-opened analogs were synthesized and tested for their ability to block the in vitro aggregation of human platelets induced by adenosine 5'-diphosphate (ADP). For the most active compounds, inhibition of the platelet aggregation triggered by arachidonic acid (AA) and ADP-induced intraplatelet calcium mobilization was also demonstrated. Based on quantitative structure-activity relationships (QSARs), we proved the impact of hydrophobicity on antiplatelet activity by a nonlinear (parabolic or bilinear) relationship between pIC(50) and lipophilicity, as assessed by RP-HPLC capacity factors and ClogP (i.e. calculated 1-octanol-water partition coefficients). This study highlighted the following additional SARs: quasi-isolipophilic isomers of 17c (isonipecotanilides and pipecolinanilides) and ring-opened analogs (e.g. anilide of beta-alanine) exhibited lower antiplatelet activity; methylation of the piperidine nitrogen of 17c has no effect, whereas alkylation with an n-propyl group decreases the activity by a factor of approximately 2, most likely due to a conformation-dependent decrease in lipophilicity.

Leisure activities are linked to mental health benefits by providing time structure: comparing employed, unemployed and homemakers.

PubMed

Goodman, William K; Geiger, Ashley M; Wolf, Jutta M

2017-01-01

Unemployment has consistently been linked to negative mental health outcomes, emphasising the need to characterise the underlying mechanisms. The current study aimed at testing whether compared with other employment groups, fewer leisure activities observed in unemployment may contribute to elevated risk for negative mental health via loss of time structure. Depressive symptoms (Center for Epidemiologic Studies Depression), leisure activities (exercise, self-focused, social), and time structure (Time Structure Questionnaire (TSQ)) were assessed cross-sectionally in 406 participants (unemployed=155, employed=140, homemakers=111) recruited through Amazon Mechanical Turk. Controlling for gender and age, structural equation modelling revealed time structure partially (employed, homemakers) and fully (unemployed) mediated the relationship between leisure activities and depressive symptoms. With the exception of differential effects for structured routines, all other TSQ factors (sense of purpose, present orientation, effective organisation and persistence) contributed significantly to all models. These findings support the idea that especially for the unemployed, leisure activities impose their mental health benefits through increasing individuals' perception of spending their time effectively. Social leisure activities that provide a sense of daily structure may thereby be a particularly promising low-cost intervention to improve mental health in this population. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Relationships between bat occupancy and habitat and landscape structure along a savanna, woodland, forest gradient in the Missouri Ozarks

Treesearch

Clarissa A. Starbuck; Sybill K. Amelon; Frank R. III Thompson

2015-01-01

Many land-management agencies are restoring savannas and woodlands using prescribed fire and forest thinning, and information is needed on how wildlife species respond to these management activities. Our objectives were to evaluate support for relationships of bat site occupancy with vegetation structure and management and landscape composition and structure across a...

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, 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.

Botulinum Neurotoxin Serotype A Inhibitors: Small-Molecule Mercaptoacetamide Analogs

PubMed Central

Moe, Scott T.; Thompson, Andrew B.; Smith, Genessa M.; Fredenburg, Ross A.; Stein, Ross L.; Jacobson, Alan R

2009-01-01

Botulinum neurotoxin elicits its paralytic activity through a zinc-dependant metalloprotease that cleaves proteins involved in neurotransmitter release. Currently, no drugs are available to reverse the effects of botulinum intoxication. Herein we report the design of a novel series of mercaptoacetamide small-molecule inhibitors active against botulinum neurotoxin serotype A. These analogs show low micromolar inhibitory activity against the isolated enzyme. Structure-activity relationship studies for a series of mercaptoacetamide analogs of 5-amino-3-phenylpyrazole reveal components essential for potent inhibitory activity. PMID:19329331

Use it or lose it: engaged lifestyle as a buffer of cognitive decline in aging?

PubMed

Hultsch, D F; Hertzog, C; Small, B J; Dixon, R A

1999-06-01

Data from the Victoria Longitudinal Study were used to examine the hypothesis that maintaining intellectual engagement through participation in everyday activities buffers individuals against cognitive decline in later life. The sample consisted of 250 middle-aged and older adults tested 3 times over 6 years. Structural equation modeling techniques were used to examine the relationships among changes in lifestyle variables and an array of cognitive variables. There was a relationship between changes in intellectually related activities and changes in cognitive functioning. These results are consistent with the hypothesis that intellectually engaging activities serve to buffer individuals against decline. However, an alternative model suggested the findings were also consistent with the hypothesis that high-ability individuals lead intellectually active lives until cognitive decline in old age limits their activities.

Quantitative structure-cytotoxicity relationship of piperic acid amides.

PubMed

Shimada, Chiyako; Uesawa, Yoshihiro; Ishihara, Mariko; Kagaya, Hajime; Kanamoto, Taisei; Terakubo, Shigemi; Nakashima, Hideki; Takao, Koichi; Miyashiro, Takaki; Sugita, Yoshiaki; Sakagami, Hiroshi

2014-09-01

A total of 12 piperic acid amides, including piperine, were subjected to quantitative structure-activity relationship (QSAR) analysis, based on their cytotoxicity, tumor selectivity and anti-HIV activity, in order to find new biological activities. Cytotoxicity against four human oral squamous cell carcinoma (OSCC) cell lines and three human oral normal cells was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Tumor selectivity was evaluated by the ratio of the mean 50% cytotoxic concentration (CC50) against normal oral cells to that against OSCC cell lines. Anti-HIV activity was evaluated by the ratio of the CC50 to 50% HIV infection-cytoprotective concentration (EC50). Physicochemical, structural, and quantum-chemical parameters were calculated based on the conformations optimized by LowModeMD method followed by density functional theory method. All compounds showed low-to-moderate tumor selectivity, but no anti-HIV activity. N-Piperoyldopamine ( 8: ) which has a catechol moiety, showed the highest tumor selectivity, possibly due to its unique molecular shape and electrostatic interaction, especially its largest partial equalization of orbital electronegativities and vsurf descriptors. The present study suggests that molecular shape and ability for electrostatic interaction are useful parameters for estimating the tumor selectivity of piperic acid amides. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Spectroscopic characteristic (FT-IR, FT-Raman, UV, 1H and 13C NMR), theoretical calculations and biological activity of alkali metal homovanillates

NASA Astrophysics Data System (ADS)

Samsonowicz, M.; Kowczyk-Sadowy, M.; Piekut, J.; Regulska, E.; Lewandowski, W.

2016-04-01

The structural and vibrational properties of lithium, sodium, potassium, rubidium and cesium homovanillates were investigated in this paper. Supplementary molecular spectroscopic methods such as: FT-IR, FT-Raman in the solid phase, UV and NMR were applied. The geometrical parameters and energies were obtained from density functional theory (DFT) B3LYP method with 6-311++G** basis set calculations. The geometry of the molecule was fully optimized, vibrational spectra were calculated and fundamental vibrations were assigned. Geometric and magnetic aromaticity indices, atomic charges, dipole moments, HOMO and LUMO energies were also calculated. The microbial activity of investigated compounds was tested against Bacillus subtilis (BS), Pseudomonas aeruginosa (PA), Escherichia coli (EC), Staphylococcus aureus (SA) and Candida albicans (CA). The relationship between the molecular structure of tested compounds and their antimicrobial activity was studied. The principal component analysis (PCA) was applied in order to attempt to distinguish the biological activities of these compounds according to selected band wavenumbers. Obtained data show that the FT-IR spectra can be a rapid and reliable analytical tool and a good source of information for the quantitative analysis of the relationship between the molecular structure of the compound and its biological activity.

Development and implementation of (Q)SAR modeling within the CHARMMing web-user interface.

PubMed

Weidlich, Iwona E; Pevzner, Yuri; Miller, Benjamin T; Filippov, Igor V; Woodcock, H Lee; Brooks, Bernard R

2015-01-05

Recent availability of large publicly accessible databases of chemical compounds and their biological activities (PubChem, ChEMBL) has inspired us to develop a web-based tool for structure activity relationship and quantitative structure activity relationship modeling to add to the services provided by CHARMMing (www.charmming.org). This new module implements some of the most recent advances in modern machine learning algorithms-Random Forest, Support Vector Machine, Stochastic Gradient Descent, Gradient Tree Boosting, so forth. A user can import training data from Pubchem Bioassay data collections directly from our interface or upload his or her own SD files which contain structures and activity information to create new models (either categorical or numerical). A user can then track the model generation process and run models on new data to predict activity. © 2014 Wiley Periodicals, Inc.

Chemical construction and structural permutation of neurotoxic natural product, antillatoxin: importance of the three-dimensional structure of the bulky side chain

PubMed Central

INOUE, Masayuki

2014-01-01

Antillatoxin 1 is a unique natural product that displays potent neurotoxic and neuritogenic activities through activation of voltage-gated sodium channels. The peptidic macrocycle of 1 was attached to a side chain with an exceptionally high degree of methylation. In this review, we discuss the total synthesis and biological evaluation of 1 and its analogues. First we describe an efficient synthetic route to 1. This strategy enabled the unified preparation of nine side chain analogues. Structure-activity relationship studies of these analogues revealed that subtle side chain modification leads to dramatic changes in activity, and detailed structural analyses indicated the importance of the overall size and three dimensional shape of the side chain. Based on these data, we designed and synthesized a photoresponsive analogue, proving that the activity of 1 was modulated via a photochemical reaction. The knowledge accumulated through these studies will be useful for the rational design of new tailor-made molecules to control the function and behavior of ion channels. PMID:24522155

Combining QSAR Modeling and Text-Mining Techniques to Link Chemical Structures and Carcinogenic Modes of Action.

PubMed

Papamokos, George; Silins, Ilona

2016-01-01

There is an increasing need for new reliable non-animal based methods to predict and test toxicity of chemicals. Quantitative structure-activity relationship (QSAR), a computer-based method linking chemical structures with biological activities, is used in predictive toxicology. In this study, we tested the approach to combine QSAR data with literature profiles of carcinogenic modes of action automatically generated by a text-mining tool. The aim was to generate data patterns to identify associations between chemical structures and biological mechanisms related to carcinogenesis. Using these two methods, individually and combined, we evaluated 96 rat carcinogens of the hematopoietic system, liver, lung, and skin. We found that skin and lung rat carcinogens were mainly mutagenic, while the group of carcinogens affecting the hematopoietic system and the liver also included a large proportion of non-mutagens. The automatic literature analysis showed that mutagenicity was a frequently reported endpoint in the literature of these carcinogens, however, less common endpoints such as immunosuppression and hormonal receptor-mediated effects were also found in connection with some of the carcinogens, results of potential importance for certain target organs. The combined approach, using QSAR and text-mining techniques, could be useful for identifying more detailed information on biological mechanisms and the relation with chemical structures. The method can be particularly useful in increasing the understanding of structure and activity relationships for non-mutagens.

Methanol oxidation reaction on core-shell structured Ruthenium-Palladium nanoparticles: Relationship between structure and electrochemical behavior

NASA Astrophysics Data System (ADS)

Kübler, Markus; Jurzinsky, Tilman; Ziegenbalg, Dirk; Cremers, Carsten

2018-01-01

In this work the relationship between structural composition and electrochemical characteristics of Palladium(Pd)-Ruthenium(Ru) nanoparticles during alkaline methanol oxidation reaction is investigated. The comparative study of a standard alloyed and a precisely Ru-core-Pd-shell structured catalyst allows for a distinct investigation of the electronic effect and the bifunctional mechanism. Core-shell catalysts benefit from a strong electronic effect and an efficient Pd utilization. It is found that core-shell nanoparticles are highly active towards methanol oxidation reaction for potentials ≥0.6 V, whereas alloyed catalysts show higher current outputs in the lower potential range. However, differential electrochemical mass spectrometry (DEMS) experiments reveal that the methanol oxidation reaction on core-shell structured catalysts proceeds via the incomplete oxidation pathway yielding formaldehyde, formic acid or methyl formate. Contrary, the alloyed catalyst benefits from the Ru atoms at its surface. Those are found to be responsible for high methanol oxidation activity at lower potentials as well as for complete oxidation of CH3OH to CO2 via the bifunctional mechanism. Based on these findings a new Ru-core-Pd-shell-Ru-terrace catalyst was synthesized, which combines the advantages of the core-shell structure and the alloy. This novel catalyst shows high methanol electrooxidation activity as well as excellent selectivity for the complete oxidation pathway.

Combining QSAR Modeling and Text-Mining Techniques to Link Chemical Structures and Carcinogenic Modes of Action

PubMed Central

Papamokos, George; Silins, Ilona

2016-01-01

There is an increasing need for new reliable non-animal based methods to predict and test toxicity of chemicals. Quantitative structure-activity relationship (QSAR), a computer-based method linking chemical structures with biological activities, is used in predictive toxicology. In this study, we tested the approach to combine QSAR data with literature profiles of carcinogenic modes of action automatically generated by a text-mining tool. The aim was to generate data patterns to identify associations between chemical structures and biological mechanisms related to carcinogenesis. Using these two methods, individually and combined, we evaluated 96 rat carcinogens of the hematopoietic system, liver, lung, and skin. We found that skin and lung rat carcinogens were mainly mutagenic, while the group of carcinogens affecting the hematopoietic system and the liver also included a large proportion of non-mutagens. The automatic literature analysis showed that mutagenicity was a frequently reported endpoint in the literature of these carcinogens, however, less common endpoints such as immunosuppression and hormonal receptor-mediated effects were also found in connection with some of the carcinogens, results of potential importance for certain target organs. The combined approach, using QSAR and text-mining techniques, could be useful for identifying more detailed information on biological mechanisms and the relation with chemical structures. The method can be particularly useful in increasing the understanding of structure and activity relationships for non-mutagens. PMID:27625608

Is the structural diversity of tripeptides sufficient for developing functional food additives with satisfactory multiple bioactivities?

NASA Astrophysics Data System (ADS)

Wang, Jian-Hui; Liu, Yong-Le; Ning, Jing-Heng; Yu, Jian; Li, Xiang-Hong; Wang, Fa-Xiang

2013-05-01

Multifunctional peptides have attracted increasing attention in the food science community because of their therapeutic potential, low toxicity and rapid intestinal absorption. However, previous study demonstrated that the limited structural variations make it difficult to optimize dipeptide molecules in a good balance between desirable and undesirable properties (F. Tian, P. Zhou, F. Lv, R. Song, Z. Li, J. Pept. Sci. 13 (2007) 549-566). In the present work, we attempt to answer whether the structural diversity is sufficient for a tripeptide to have satisfactory multiple bioactivities. Statistical test, structural examination and energetic analysis confirm that peptides of three amino acids long can bind tightly to human angiotensin converting enzyme (ACE) and thus exert significant antihypertensive efficacy. Further quantitative structure-activity relationship (QSAR) modeling and prediction of all 8000 possible tripeptides reveal that their ACE-inhibitory potency exhibits a good (positive) relationship to antioxidative activity, but has only a quite modest correlation with bitterness. This means that it is possible to find certain tripeptide entities possessing the optimal combination of strong ACE-inhibitory potency, high antioxidative activity and weak bitter taste, which are the promising candidates for developing multifunctional food additives with satisfactory multiple bioactivities. The marked difference between dipeptide and tripeptide can be attributed to the fact that the structural diversity of peptides increases dramatically with a slight change in sequence length.

Network-Level Structure-Function Relationships in Human Neocortex

PubMed Central

Mišić, Bratislav; Betzel, Richard F.; de Reus, Marcel A.; van den Heuvel, Martijn P.; Berman, Marc G.; McIntosh, Anthony R.; Sporns, Olaf

2016-01-01

The dynamics of spontaneous fluctuations in neural activity are shaped by underlying patterns of anatomical connectivity. While numerous studies have demonstrated edge-wise correspondence between structural and functional connections, much less is known about how large-scale coherent functional network patterns emerge from the topology of structural networks. In the present study, we deploy a multivariate statistical technique, partial least squares, to investigate the association between spatially extended structural networks and functional networks. We find multiple statistically robust patterns, reflecting reliable combinations of structural and functional subnetworks that are optimally associated with one another. Importantly, these patterns generally do not show a one-to-one correspondence between structural and functional edges, but are instead distributed and heterogeneous, with many functional relationships arising from nonoverlapping sets of anatomical connections. We also find that structural connections between high-degree hubs are disproportionately represented, suggesting that these connections are particularly important in establishing coherent functional networks. Altogether, these results demonstrate that the network organization of the cerebral cortex supports the emergence of diverse functional network configurations that often diverge from the underlying anatomical substrate. PMID:27102654

Design and Synthesis of Mannich bases as Benzimidazole Derivatives as Analgesic Agents.

PubMed

Datar, Prasanna A; Limaye, Saleel A

2015-01-01

Mannich bases were selected for 2D QSAR study to derive meaningful relationship between the structural features and analgesic activity. Using the knowledge of important features a novel series was designed to obtain improved analgesic activity. A series of novel Mannich bases 1-(N-substituted amino)methyl]-2-substituted benzimidazole derivatives were synthesized and were screened for analgesic activity. Some of these compounds showed promising analgesic activity when compared with the standard drug diclofenac sodium.

Descriptors of Oxygen-Evolution Activity for Oxides: A Statistical Evaluation

DOE PAGES

Hong, Wesley T.; Welsch, Roy E.; Shao-Horn, Yang

2015-12-16

Catalysts for oxygen electrochemical processes are critical for the commercial viability of renewable energy storage and conversion devices such as fuel cells, artificial photosynthesis, and metal-air batteries. Transition metal oxides are an excellent system for developing scalable, non-noble-metal-based catalysts, especially for the oxygen evolution reaction (OER). Central to the rational design of novel catalysts is the development of quantitative structure-activity relation-ships, which correlate the desired catalytic behavior to structural and/or elemental descriptors of materials. The ultimate goal is to use these relationships to guide materials design. In this study, 101 intrinsic OER activities of 51 perovskites were compiled from fivemore » studies in literature and additional measurements made for this work. We explored the behavior and performance of 14 descriptors of the metal-oxygen bond strength using a number of statistical approaches, including factor analysis and linear regression models. We found that these descriptors can be classified into five descriptor families and identify electron occupancy and metal-oxygen covalency as the dominant influences on the OER activity. However, multiple descriptors still need to be considered in order to develop strong predictive relationships, largely outperforming the use of only one or two descriptors (as conventionally done in the field). Here, we confirmed that the number of d electrons, charge-transfer energy (covalency), and optimality of eg occupancy play the important roles, but found that structural factors such as M-O-M bond angle and tolerance factor are relevant as well. With these tools, we demonstrate how statistical learning can be used to draw novel physical insights and combined with data mining to rapidly screen OER electrocatalysts across a wide chemical space.« less

Effect of Substitution on the Aniline Moiety of the GPR88 Agonist 2-PCCA: Synthesis, Structure-Activity Relationships, and Molecular Modeling Studies.

PubMed

Jin, Chunyang; Decker, Ann M; Harris, Danni L; Blough, Bruce E

2016-10-19

GPR88, an orphan receptor richly expressed in the striatum, is implicated in a number of basal ganglia-associated disorders. In order to elucidate the functions of GPR88, an in vivo probe appropriate for CNS investigation is required. We previously reported that 2-PCCA was able to modulate GPR88-mediated cAMP production through a Gα i -coupled pathway. Early structure-activity relationship (SAR) studies suggested that the aniline moiety of 2-PCCA is a suitable site for diverse modifications. Aimed at elucidating structural requirements in this region, we have designed and synthesized a series of analogues bearing a variety of substituents at the phenyl ring of the aniline moiety. Several compounds (e.g., 5j, 5o) showed improved or comparable potency, but have lower lipophilicity than 2-PCCA (clogP 6.19). These compounds provide the basis for further optimization to probe GPR88 in vivo functions. Computational studies confirmed the SAR trends and supported the notion that 4'-substituents on the biphenyl ring exit through a largely hydrophobic binding site to the extracellular loop.

Relationship between the lipophilicity of gallic acid n-alquil esters' derivatives and both myeloperoxidase activity and HOCl scavenging.

PubMed

Rosso, Rober; Vieira, Tiago O; Leal, Paulo C; Nunes, Ricardo J; Yunes, Rosendo A; Creczynski-Pasa, Tânia B

2006-09-15

The gallic acid and several n-alkyl gallates, with the same number of hydroxyl substituents, varying only in the side carbonic chain length, with respective lipophilicity defined through the C log P, were studied. It evidenced the structure-activity relationship of the myeloperoxidase activity inhibition and the hypochlorous acid scavenger property, as well as its low toxicity in rat hepatic tissue. The gallates with C log P below 3.0 (compounds 2-7) were more active against the enzyme activity, what means that the addition of 1-6 carbons (C log P between 0.92 and 2.92) at the side chain increased approximately 50% the gallic acid effect. However, a relationship between the HOCl scavenging capability and the lipophilicity was not observed. With these results it is possible to suggest that the gallates protect the HOCl targets through two mechanisms: inhibiting its production by the enzyme and scavenging the reactive specie.

A comprehensive analysis of the thermodynamic events involved in ligand receptor binding using CoRIA and its variants

NASA Astrophysics Data System (ADS)

Verma, Jitender; Khedkar, Vijay M.; Prabhu, Arati S.; Khedkar, Santosh A.; Malde, Alpeshkumar K.; Coutinho, Evans C.

2008-02-01

Quantitative Structure-Activity Relationships (QSAR) are being used since decades for prediction of biological activity, lead optimization, classification, identification and explanation of the mechanisms of drug action, and prediction of novel structural leads in drug discovery. Though the technique has lived up to its expectations in many aspects, much work still needs to be done in relation to problems related to the rational design of peptides. Peptides are the drugs of choice in many situations, however, designing them rationally is a complicated task and the complexity increases with the length of their sequence. In order to deal with the problem of peptide optimization, one of our recently developed QSAR formalisms CoRIA (Comparative Residue Interaction Analysis) is being expanded and modified as: reverse-CoRIA ( rCoRIA) and mixed-CoRIA ( mCoRIA) approaches. In these methodologies, the peptide is fragmented into individual units and the interaction energies (van der Waals, Coulombic and hydrophobic) of each amino acid in the peptide with the receptor as a whole ( rCoRIA) and with individual active site residues in the receptor ( mCoRIA) are calculated, which along with other thermodynamic descriptors, are used as independent variables that are correlated to the biological activity by chemometric methods. As a test case, the three CoRIA methodologies have been validated on a dataset of diverse nonamer peptides that bind to the Class I major histocompatibility complex molecule HLA-A*0201, and for which some structure activity relationships have already been reported. The different models developed, and validated both internally as well as externally, were found to be robust with statistically significant values of r 2 (correlation coefficient) and r 2 pred (predictive r 2). These models were able to identify all the structure activity relationships known for this class of peptides, as well uncover some new relationships. This means that these methodologies will perform well for other peptide datasets too. The major advantage of these approaches is that they explicitly utilize the 3D structures of small molecules or peptides as well as their macromolecular targets, to extract position-specific information about important interactions between the ligand and receptor, which can assist the medicinal and computational chemists in designing new molecules, and biologists in studying the influence of mutations in the target receptor on ligand binding.

Reasoning Activity for Smart Homes Using a Lattice-Based Evidential Structure

NASA Astrophysics Data System (ADS)

Liao, Jing; Bi, Yaxin; Nugent, Chris

This paper explores a revised evidential lattice structure designed for the purposes of activity recognition within Smart Homes. The proposed structure consists of three layers, an object layer, a context layer and an activity layer. These layers can be used to combine the mass functions derived from sensors along with sensor context and can subsequently be used to infer activities. We present the details of configuring the activity recognition process and perform an analysis on the relationship between the number of sensors and the number of layers. We also present the details of an empirical study on two public data sets. The results from this work has demonstrated that the proposed method is capable of correctly detecting activities with a high degree of accuracy (84.27%) with a dataset from MIT [4] and 82.49% with a dataset from the University of Amsterdam[10].

Discovery of core-structurally novel PTP1B inhibitors with specific selectivity containing oxindole-fused spirotetrahydrofurochroman by one-pot reaction.

PubMed

Dong, Suzhen; Lei, Yubing; Jia, Shikun; Gao, Lixin; Li, Jia; Zhu, Tong; Liu, Shunying; Hu, Wenhao

2017-02-15

Protein tyrosine phosphatase 1B (PTP1B) has been proposed to be an ideal target for treatment of type II diabetes and obesity. However, no druggable PTP1B inhibitor has been established and there is still an urgent demand for the development of structurally novel PTPIB inhibitor. Herein, we reported core-structurally novel PTP1B inhibitors with low micromole-ranged inhibitory activity by one-pot reaction from simple starting materials. Further studies demonstrated some of these active compounds had a specific selectivity over other PTPs. The structure and activity relationship was also described. The best active and selective compound 5e inhibited PTP1B activity with an IC 50 of 4.53μM. Molecular docking analysis further demonstrated that compound 5e bound to the active pocket of PTP1B. The results might provide some insights for further development of new drugs for type II diabetes and obesity. Copyright © 2016 Elsevier Ltd. All rights reserved.

Design and synthesis of novel 2-(indol-5-yl)thiazole derivatives as xanthine oxidase inhibitors.

PubMed

Song, Jeong Uk; Choi, Sung Pil; Kim, Tae Hun; Jung, Cheol-Kyu; Lee, Joo-Youn; Jung, Sang-Hun; Kim, Geun Tae

2015-03-15

Xanthine oxidase (XO) inhibitors have been widely used for the treatment of gout. Indole rings are frequently used as active scaffold in designing inhibitors for enzymes. Herein, we describe the structure-activity relationship for novel xanthine oxidase inhibitors based on indole scaffold. A series of novel tri-substituted 2-(indol-5-yl)thiazole derivatives were synthesized, and their in vitro inhibitory activities against xanthine oxidase and in vivo efficacy lowering uric acid level in blood were measured. Among them, 2-(3-cyano-2-isopropylindol-5-yl)-4-methylthiazole-5-carboxylic acid exhibits the most potent XO inhibitory activity (IC50 value: 3.5nM) and the excellent plasma uric acid lowering activity. Study of structure activity relationship indicated that hydrophobic moiety (e.g., isopropyl) at 1-position and electron withdrawing group (e.g., CN) at 3-position of indole ring and small hydrophobic group (CH3) at 4-position of the thiazole ring enhanced the XO inhibitory activity. Hydrophobic substitution such as isopropyl at 1-position of the indole moiety without any substitution at 2-position has an essential role for enhancing bioavailability and therefore for high in vivo efficacy. Copyright © 2015 Elsevier Ltd. All rights reserved.

It's like balancing on a slackline - A description of how adults with congenital heart disease describe themselves in relation to physical activity.

PubMed

Bay, Annika; Lämås, Kristina; Berghammer, Malin; Sandberg, Camilla; Johansson, Bengt

2018-05-12

To illuminate how adults with CHD describe themselves in relation to physical activity. Several studies have shown that adults with congenital heart disease (CHD) have reduced exercise capacity and do not reach the recommended daily level of physical activity. With this in view, it is of immense importance to investigate how this population experiences physical activity. Qualitative study with semi-structured interviews analysed with qualitative content analysis. Semi-structured interviews were individually performed with fourteen adults (women=7, age 19-68 years) with complex CHD. Patients were purposively recruited from the clinic waiting list, based on a scheduled follow-up and diagnosis. The overall theme, It's like balancing on a slackline, illustrates how adults with CHD described themselves in relation to physical activity. This overall theme consisted of four subthemes: (1) Being an adventurer- enjoying the challenges of physical activity; (2) Being a realist- adapting to physical ability; (3) Being a non-doer- lacking prerequisites for physical activity; and (4) Being an outsider- feeling excluded depending on physical ability. Adults with CHD seem to have a diverse relationship to physical activity and it involves various aspects throughout the lifespan. The findings point out factors that might constitute as obstacles for being physically active, specific for people with chronic conditions like CHD. This highlights the importance of further exploring the hindering and facilitating factors for being physically active in order to get a deeper understanding of how to support adults with CHD to be physically active. Given the diverse relationship to physical activity, nurses have to further investigate the patients' relationship to physical activity, in order to support a healthy lifestyle. Nurses and allied health professionals should offer individualized exercise prescriptions and education about suitable physical activities in relation to physical ability. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Lead optimization of a pyridine-carboxamide series as DGAT-1 inhibitors.

PubMed

Ting, Pauline C; Lee, Joe F; Zorn, Nicolas; Kim, Hyunjin M; Aslanian, Robert G; Lin, Mingxiang; Smith, Michelle; Walker, Scott S; Cook, John; Van Heek, Margaret; Lachowicz, Jean

2013-02-15

The structure-activity relationship studies of a novel series of carboxylic acid derivatives of pyridine-carboxamides as DGAT-1 inhibitors is described. The optimization of the initial lead compound 6 based on in vitro and in vivo activity led to the discovery of key compounds 10j and 17h. Copyright © 2013 Elsevier Ltd. All rights reserved.

Relative activity of cerebral subcortical gray matter in varying states of attention and awareness in normal subjects and patient studies

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

Cooper, M.; Chen, C.T.; Levy, J.

1985-05-01

An important aspect of the study of brain function involves measurement of the relationships; between activities in the subcortical gray matter of the caudate and of the thalamus; and between these structures and functional cortical areas. The authors have studied these relationships in 22 subjects under different conditions of activation, sleep and sensory deprivation using a PET VI system and F-18-2DG to determine regional cerebral metabolism. Subject activating conditions were maintained throughout the period of equilibration of F-18-2DG and E.E.G.'s were monitored. Multiple tomographic slices of 1-2 million counts were obtained simultaneously with slice separation of 14mm and each planemore » parallel to the cantho-meatal line. In activated and non-activated awake conditions for normal subjects, left and right thalmus-to-caudate ratios were similar and greater than unity. This relationship was maintained in non-REM sleep, but was reversed and divergent in REM sleep and sensory deprivation; this was also evident in 3/4 narcoleptics awake and asleep in non-REM and REM and 2/3 schizophrenics and affective disorder, subjects. This approach appears to have potential for characterizating normal and disordered regional cerebral function.« less

Trithiocarbonates: exploration of a new head group for HDAC inhibitors.

PubMed

Dehmel, Florian; Ciossek, Thomas; Maier, Thomas; Weinbrenner, Steffen; Schmidt, Beate; Zoche, Martin; Beckers, Thomas

2007-09-01

Inhibition of histone deacetylases class I/II enzymes is a new, promising approach for cancer therapy. In the present study, we disclose a new structural class of HDAC inhibitors with the trithiocarbonate motif. A clear structure-activity-relationship was obtained for the cap-linker motif and the putative Zn(2+) complexing head group. Selected analogs display potent inhibition of HDAC enzymatic activity and a cellular potency comparable to that of suberoylanilide hydroxamic acid (SAHA), recently approved for treatment of patients with advanced cutaneous T-cell lymphoma.

Simulated Screens of DNA Encoded Libraries: The Potential Influence of Chemical Synthesis Fidelity on Interpretation of Structure-Activity Relationships.

PubMed

Satz, Alexander L

2016-07-11

Simulated screening of DNA encoded libraries indicates that the presence of truncated byproducts complicates the relationship between library member enrichment and equilibrium association constant (these truncates result from incomplete chemical reactions during library synthesis). Further, simulations indicate that some patterns observed in reported experimental data may result from the presence of truncated byproducts in the library mixture and not structure-activity relationships. Potential experimental methods of minimizing the presence of truncates are assessed via simulation; the relationship between enrichment and equilibrium association constant for libraries of differing purities is investigated. Data aggregation techniques are demonstrated that allow for more accurate analysis of screening results, in particular when the screened library contains significant quantities of truncates.

Photocatalytic activity of silver oxide capped Ag nanoparticles constructed by air plasma irradiation

NASA Astrophysics Data System (ADS)

Fang, Yingcui; Wu, Qingmeng; Li, Huanhuan; Zhang, Bing; Yan, Rong; Chen, Junling; Sun, Mengtao

2018-04-01

We construct a kind of structure of silver oxide capped silver nanoparticles (AgNPs) by cost-efficient air plasma irradiation, and study its visible-light driven photocatalytic activity (PA). By controlling the oxidization time, the relationship between the intensity of the localized surface plasmon resonance (LSPR) and the PA is well established. The PA reaches the maximum when the LSPR of AgNPs is nearly completely damped (according to absorption spectra); however, under this condition, the LSPR still works, confirmed with the high efficient selective transformation of p-Aminothiophenol (PATP) to p, p'-dimercaptoazobenzene (DMAB) under visible light. The mechanism of the LSPR damping induced PA improvement is discussed. We not only provide a cost-efficient approach to construct a LSPR strong damping structure but also promote the understanding of LSPR strong damping and its relationship with photocatalysis.

The Significance of G Protein-Coupled Receptor Crystallography for Drug Discovery

PubMed Central

Salon, John A.; Lodowski, David T.

2011-01-01

Crucial as molecular sensors for many vital physiological processes, seven-transmembrane domain G protein-coupled receptors (GPCRs) comprise the largest family of proteins targeted by drug discovery. Together with structures of the prototypical GPCR rhodopsin, solved structures of other liganded GPCRs promise to provide insights into the structural basis of the superfamily's biochemical functions and assist in the development of new therapeutic modalities and drugs. One of the greatest technical and theoretical challenges to elucidating and exploiting structure-function relationships in these systems is the emerging concept of GPCR conformational flexibility and its cause-effect relationship for receptor-receptor and receptor-effector interactions. Such conformational changes can be subtle and triggered by relatively small binding energy effects, leading to full or partial efficacy in the activation or inactivation of the receptor system at large. Pharmacological dogma generally dictates that these changes manifest themselves through kinetic modulation of the receptor's G protein partners. Atomic resolution information derived from increasingly available receptor structures provides an entrée to the understanding of these events and practically applying it to drug design. Supported by structure-activity relationship information arising from empirical screening, a unified structural model of GPCR activation/inactivation promises to both accelerate drug discovery in this field and improve our fundamental understanding of structure-based drug design in general. This review discusses fundamental problems that persist in drug design and GPCR structural determination. PMID:21969326

Hydrothermal fluids circulation and travertine deposition in an active tectonic setting: Insights from the Kamara geothermal area (western Anatolia, Turkey)

NASA Astrophysics Data System (ADS)

Brogi, Andrea; Alçiçek, M. Cihat; Yalçıner, Cahit Çağlar; Capezzuoli, Enrico; Liotta, Domenico; Meccheri, Marco; Rimondi, Valentina; Ruggieri, Giovanni; Gandin, Anna; Boschi, Chiara; Büyüksaraç, Aydin; Alçiçek, Hülya; Bülbül, Ali; Baykara, Mehmet Oruç; Shen, Chuan-Chou

2016-06-01

Coexistence of thermal springs, travertine deposits and tectonic activity is a recurring feature for most geothermal areas. Although such a certainty, their relationships are debated mainly addressing on the role of the tectonic activity in triggering and controlling fluids flow and travertine deposition. In this paper, we present the results of an integrated study carried out in a geothermal area located in western Anatolia (Turkey), nearby the well-known Pamukkale area (Denizli Basin). Our study focused on the relationships among hydrothermal fluids circulation, travertine deposition and tectonic activity, with particular emphasis on the role of faults in controlling fluids upwelling, thermal springs location and deposition of travertine masses. New field mapping and structural/kinematics analyses allowed us to recognize two main faults systems (NW- and NE-trending), framed in the Neogene-Quaternary extensional tectonic evolution of western Anatolia. A geo-radar (GPR) prospection was also provided in a key-area, permitting us to reconstruct a buried fault zone and its relationships with the development of a fissure-ridge travertine deposit (Kamara fissure-ridge). The integration among structural and geophysical studies, fluids inclusion, geochemical, isotopic data and 230 Th/238 U radiometric age determination on travertine deposits, depict the characteristics of the geothermal fluids and their pathway, up to the surface. Hydrological and seismological data have been also taken in account to investigate the relation between local seismicity and fluid upwelling. As a main conclusion we found strict relationships among tectonic activity, earthquakes occurrence, and variation of the physical/chemical features of the hydrothermal fluids, presently exploited at depth, or flowing out in thermal springs. In the same way, we underline the tectonic role in controlling the travertine deposition, making travertine (mainly banded travertine) a useful proxy to reconstruct the seismological history of an area, as well as the characteristics of the parent geothermal fluids, adding an effective tool for geothermal exploration tasks.

Discovery and structure-based design of 4,6-diaminonicotinamides as potent and selective IRAK4 inhibitors

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

Bhide, Rajeev S.; Keon, Alec; Weigelt, Carolyn

2017-11-01

The identification of small molecule inhibitors of IRAK4 for the treatment of autoimmune diseases has been an area of intense research. We discovered novel 4,6-diaminonicotinamides which potently inhibit IRAK4. Optimization efforts were aided by X-ray crystal structures of inhibitors bound to IRAK4. Structure activity relationship (SAR) studies led to the identification of compound 29 which exhibited sub-micromolar potency in a LTA stimulated cellular assay.

Structural Dynamics and Activity of Nanocatalysts Inside Fuel Cells by in-operando Atomic Pair Distribution Studies

NASA Astrophysics Data System (ADS)

Prasai, Binay

We present the results from a study aimed at clarifying the relationship between the atomic structure and activity of nanocatalysts for chemical reactions driving fuel cells, such as the oxygen reduction reaction (ORR). Using in-operando high-energy X-ray diffraction we tracked the evolution of the atomic structure and activity of noble metal-transition metal(NM-TM) nanocatalysts for ORR as they function at the cathode of a fully operational proton exchange membrane fuel cell (PEMFC). Data were analyzed in terms of atomic pair distribution functions and compared to the current output of the PEMFC, which was also recorded during the experiments. The comparison revealed that under actual operating conditions, NM-TM nanocatalysts can undergo structural changes that differ significantly in both length-scale and dynamics and so can suffer losses in their ORR activity that differ significantly in both character and magnitude. Therefore, we argue that strategies for reducing ORR activity losses should implement steps for achieving control not only over the length but also over the time-scale of the structural changes of NM-TM NPs that indeed occur during PEMFC operation.

SAR STUDY OF NASAL TOXICITY: LESSONS FOR MODELING SMALL TOXICITY DATASETS

EPA Science Inventory

Most toxicity data, particularly from whole animal bioassays, are generated without the needs or capabilities of structure-activity relationship (SAR) modeling in mind. Some toxicity endpoints have been of sufficient regulatory concern to warrant large scale testing efforts (e.g....

Is There Consistency between the Binding Affinity and Inhibitory Potential of Natural Polyphenols as α-amylase Inhibitors?

PubMed

Xu, Wei; Shao, Rong; Xiao, Jianbo

2016-07-26

The inhibitory potential of natural polyphenols for α-amylases has attracted great interests among researchers. The structure-affinity properties of natural polyphenols binding to α-amylase and the structure-activity relationship of dietary polyphenols inhibiting α-amylase were deeply investigated. There is a lack of consistency between the structure-affinity relationship and the structure-activity relationship of natural polyphenols as α-amylase inhibitors. Is it consistent between the binding affinity and inhibitory potential of natural polyphenols as with α-amylase inhibitors? It was found that the consistency between the binding affinity and inhibitory potential of natural polyphenols as with α-amylase inhibitors is not equivocal. For example, there is no consistency between the binding affinity and the inhibitory potential of quercetin and its glycosides as α-amylase inhibitors. However, catechins with higher α-amylase inhibitory potential exhibited higher affinity with α-amylase.

Testing Nucleoside Analogues as Inhibitors of Bacillus anthracis Spore Germination In Vitro and in Macrophage Cell Culture ▿

PubMed Central

Alvarez, Zadkiel; Lee, Kyungae; Abel-Santos, Ernesto

2010-01-01

Bacillus anthracis, the etiological agent of anthrax, has a dormant stage in its life cycle known as the endospore. When conditions become favorable, spores germinate and transform into vegetative bacteria. In inhalational anthrax, the most fatal manifestation of the disease, spores enter the organism through the respiratory tract and germinate in phagosomes of alveolar macrophages. Germinated cells can then produce toxins and establish infection. Thus, germination is a crucial step for the initiation of pathogenesis. B. anthracis spore germination is activated by a wide variety of amino acids and purine nucleosides. Inosine and l-alanine are the two most potent nutrient germinants in vitro. Recent studies have shown that germination can be hindered by isomers or structural analogues of germinants. 6-Thioguanosine (6-TG), a guanosine analogue, is able to inhibit germination and prevent B. anthracis toxin-mediated necrosis in murine macrophages. In this study, we screened 46 different nucleoside analogues as activators or inhibitors of B. anthracis spore germination in vitro. These compounds were also tested for their ability to protect the macrophage cell line J774a.1 from B. anthracis cytotoxicity. Structure-activity relationship analysis of activators and inhibitors clarified the binding mechanisms of nucleosides to B. anthracis spores. In contrast, no structure-activity relationships were apparent for compounds that protected macrophages from B. anthracis-mediated killing. However, multiple inhibitors additively protected macrophages from B. anthracis. PMID:20921305

Structural Modifications of Benzimidazoles via Multi-Step Synthesis and Their Impact on Sirtuin-Inhibitory Activity.

PubMed

Yoon, Yeong Keng; Choon, Tan Soo

2016-01-01

Benzimidazole derivatives have been shown to possess sirtuin-inhibitory activity. In the continuous search for potent sirtuin inhibitors, systematic changes on the terminal benzene ring were performed on previously identified benzimidazole-based sirtuin inhibitors, to further investigate their structure-activity relationships. It was demonstrated that the sirtuin activities of these novel compounds followed the trend where meta-substituted compounds possessed markedly weaker potency than ortho- and para-substituted compounds, with the exception of halogenated substituents. Molecular docking studies were carried out to rationalize these observations. Apart from this, the methods used to synthesize the interesting compounds are also discussed. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

First discovery of insecticidal activity of 9,9'-epoxylignane and dihydroguaiaretic acid against houseflies and the structure-activity relationship.

PubMed

Wukirsari, Tuti; Nishiwaki, Hisashi; Hasebe, Ayaka; Shuto, Yoshihiro; Yamauchi, Satoshi

2013-05-08

The insecticidal activity of (-)-(8R,8'R)-3,3'-dimethoxy-9,9'-epoxylignane-4,4'-diol (1) against houseflies was clarified for the first time. The activities of other stereoisomers were weaker than that of the (8R,8'R)-stereoisomer. In the course of research into structure-activity relationships involving 30 newly synthesized (8R,8'R)-derivatives, 5-fold higher activity (ED50 = 0.91 nmol/fly) was observed for (-)-(8R,8'R)-3,3',4-trimethoxy-9,9'-epoxylignan-4'-ol (21) than for the naturally occurring compound (1). The activity of 1 was weaker than that of (-)-(8R,8'R)-dihydroguaiaretic acid ((-)-DGA) (4); however, compound 21 showed almost the same level of activity as 4.

Atomic Scale Structure-Chemistry Relationships at Oxide Catalyst Surfaces and Interfaces

NASA Astrophysics Data System (ADS)

McBriarty, Martin E.

Oxide catalysts are integral to chemical production, fuel refining, and the removal of environmental pollutants. However, the atomic-scale phenomena which lead to the useful reactive properties of catalyst materials are not sufficiently understood. In this work, the tools of surface and interface science and electronic structure theory are applied to investigate the structure and chemical properties of catalytically active particles and ultrathin films supported on oxide single crystals. These studies focus on structure-property relationships in vanadium oxide, tungsten oxide, and mixed V-W oxides on the surfaces of alpha-Al2O3 and alpha-Fe2O 3 (0001)-oriented single crystal substrates, two materials with nearly identical crystal structures but drastically different chemical properties. In situ synchrotron X-ray standing wave (XSW) measurements are sensitive to changes in the atomic-scale geometry of single crystal model catalyst surfaces through chemical reaction cycles, while X-ray photoelectron spectroscopy (XPS) reveals corresponding chemical changes. Experimental results agree with theoretical calculations of surface structures, allowing for detailed electronic structure investigations and predictions of surface chemical phenomena. The surface configurations and oxidation states of V and W are found to depend on the coverage of each, and reversible structural shifts accompany chemical state changes through reduction-oxidation cycles. Substrate-dependent effects suggest how the choice of oxide support material may affect catalytic behavior. Additionally, the structure and chemistry of W deposited on alpha-Fe 2O3 nanopowders is studied using X-ray absorption fine structure (XAFS) measurements in an attempt to bridge single crystal surface studies with real catalysts. These investigations of catalytically active material surfaces can inform the rational design of new catalysts for more efficient and sustainable chemistry.

Heparin/heparan sulfate 6-O-sulfatase from Flavobacterium heparinum: integrated structural and biochemical investigation of enzyme active site and substrate specificity.

PubMed

Myette, James R; Soundararajan, Venkataramanan; Shriver, Zachary; Raman, Rahul; Sasisekharan, Ram

2009-12-11

Heparin and heparan sulfate glycosaminoglycans (HSGAGs) comprise a chemically heterogeneous class of sulfated polysaccharides. The development of structure-activity relationships for this class of polysaccharides requires the identification and characterization of degrading enzymes with defined substrate specificity and enzymatic activity. Toward this end, we report here the molecular cloning and extensive structure-function analysis of a 6-O-sulfatase from the Gram-negative bacterium Flavobacterium heparinum. In addition, we report the recombinant expression of this enzyme in Escherichia coli in a soluble, active form and identify it as a specific HSGAG sulfatase. We further define the mechanism of action of the enzyme through biochemical and structural studies. Through the use of defined substrates, we investigate the kinetic properties of the enzyme. This analysis was complemented by homology-based molecular modeling studies that sought to rationalize the substrate specificity of the enzyme and mode of action through an analysis of the active-site topology of the enzyme including identifying key enzyme-substrate interactions and assigning key amino acids within the active site of the enzyme. Taken together, our structural and biochemical studies indicate that 6-O-sulfatase is a predominantly exolytic enzyme that specifically acts on N-sulfated or N-acetylated 6-O-sulfated glucosamines present at the non-reducing end of HSGAG oligosaccharide substrates. This requirement for the N-acetyl or N-sulfo groups on the glucosamine substrate can be explained through eliciting favorable interactions with key residues within the active site of the enzyme. These findings provide a framework that enables the use of 6-O-sulfatase as a tool for HSGAG structure-activity studies as well as expand our biochemical and structural understanding of this important class of enzymes.

Key structural features of nonsteroidal ligands for binding and activation of the androgen receptor.

PubMed

Yin, Donghua; He, Yali; Perera, Minoli A; Hong, Seoung Soo; Marhefka, Craig; Stourman, Nina; Kirkovsky, Leonid; Miller, Duane D; Dalton, James T

2003-01-01

The purposes of the present studies were to examine the androgen receptor (AR) binding ability and in vitro functional activity of multiple series of nonsteroidal compounds derived from known antiandrogen pharmacophores and to investigate the structure-activity relationships (SARs) of these nonsteroidal compounds. The AR binding properties of sixty-five nonsteroidal compounds were assessed by a radioligand competitive binding assay with the use of cytosolic AR prepared from rat prostates. The AR agonist and antagonist activities of high-affinity ligands were determined by the ability of the ligand to regulate AR-mediated transcriptional activation in cultured CV-1 cells, using a cotransfection assay. Nonsteroidal compounds with diverse structural features demonstrated a wide range of binding affinity for the AR. Ten compounds, mainly from the bicalutamide-related series, showed a binding affinity superior to the structural pharmacophore from which they were derived. Several SARs regarding nonsteroidal AR binding were revealed from the binding data, including stereoisomeric conformation, steric effect, and electronic effect. The functional activity of high-affinity ligands ranged from antagonist to full agonist for the AR. Several structural features were found to be determinative of agonist and antagonist activities. The nonsteroidal AR agonists identified from the present studies provided a pool of candidates for further development of selective androgen receptor modulators (SARMs) for androgen therapy. Also, these studies uncovered or confirmed numerous important SARs governing AR binding and functional properties by nonsteroidal molecules, which would be valuable in the future structural optimization of SARMs.

Cytotoxic and antifungal activities of melleolide antibiotics follow dissimilar structure-activity relationships.

PubMed

Bohnert, Markus; Nützmann, Hans-Wilhelm; Schroeckh, Volker; Horn, Fabian; Dahse, Hans-Martin; Brakhage, Axel A; Hoffmeister, Dirk

2014-09-01

The fungal genus Armillaria is unique in that it is the only natural source of melleolide antibiotics, i.e., protoilludene alcohols esterified with orsellinic acid or its derivatives. This class of natural products is known to exert antimicrobial and cytotoxic effects. Here, we present a refined relationship between the structure and the antimicrobial activity of the melleolides. Using both agar diffusion and broth dilution assays, we identified the Δ(2,4)-double bond of the protoilludene moiety as a key structural feature for antifungal activity against Aspergillus nidulans, Aspergillus flavus, and Penicillium notatum. These findings contrast former reports on cytotoxic activities and may indicate a different mode of action towards susceptible fungi. We also report the isolation and structure elucidation of five melleolides (6'-dechloroarnamial, 6'-chloromelleolide F, 10-hydroxy-5'-methoxy-6'-chloroarmillane, and 13-deoxyarmellides A and B), along with the finding that treatment with an antifungal melleolide impacts transcription of A. nidulans natural product genes. Copyright © 2014 Elsevier Ltd. All rights reserved.

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.

Positive Modulators of the N-Methyl-d-aspartate Receptor: Structure-Activity Relationship Study of Steroidal 3-Hemiesters.

PubMed

Krausova, Barbora; Slavikova, Barbora; Nekardova, Michaela; Hubalkova, Pavla; Vyklicky, Vojtech; Chodounska, Hana; Vyklicky, Ladislav; Kudova, Eva

2018-05-24

Here, we report the synthesis of pregn-5-ene and androst-5-ene dicarboxylic acid esters and explore the structure-activity relationship (SAR) for their modulation of N-methyl-d-aspartate receptors (NMDARs). All compounds were positive modulators of recombinant GluN1/GluN2B receptors (EC 50 varying from 1.8 to 151.4 μM and E max varying from 48% to 452%). Moreover, 10 compounds were found to be more potent GluN1/GluN2B receptor modulators than endogenous pregnenolone sulfate (EC 50 = 21.7 μM). The SAR study revealed a relationship between the length of the residues at carbon C-3 of the steroid molecule and the positive modulatory effect at GluN1/GluN2B receptors for various D-ring modifications. A selected compound, 20-oxo-pregnenolone hemiadipate, potentiated native NMDARs to a similar extent as GluN1/GluN2A-D receptors and inhibited AMPARs and GABA A R responses. These results provide a unique opportunity for the development of new steroid based drugs with potential use in the treatment of neuropsychiatric disorders involving hypofunction of NMDARs.

Segregation and Integration of Auditory Streams when Listening to Multi-Part Music

PubMed Central

Ragert, Marie; Fairhurst, Merle T.; Keller, Peter E.

2014-01-01

In our daily lives, auditory stream segregation allows us to differentiate concurrent sound sources and to make sense of the scene we are experiencing. However, a combination of segregation and the concurrent integration of auditory streams is necessary in order to analyze the relationship between streams and thus perceive a coherent auditory scene. The present functional magnetic resonance imaging study investigates the relative role and neural underpinnings of these listening strategies in multi-part musical stimuli. We compare a real human performance of a piano duet and a synthetic stimulus of the same duet in a prioritized integrative attention paradigm that required the simultaneous segregation and integration of auditory streams. In so doing, we manipulate the degree to which the attended part of the duet led either structurally (attend melody vs. attend accompaniment) or temporally (asynchronies vs. no asynchronies between parts), and thus the relative contributions of integration and segregation used to make an assessment of the leader-follower relationship. We show that perceptually the relationship between parts is biased towards the conventional structural hierarchy in western music in which the melody generally dominates (leads) the accompaniment. Moreover, the assessment varies as a function of both cognitive load, as shown through difficulty ratings and the interaction of the temporal and the structural relationship factors. Neurally, we see that the temporal relationship between parts, as one important cue for stream segregation, revealed distinct neural activity in the planum temporale. By contrast, integration used when listening to both the temporally separated performance stimulus and the temporally fused synthetic stimulus resulted in activation of the intraparietal sulcus. These results support the hypothesis that the planum temporale and IPS are key structures underlying the mechanisms of segregation and integration of auditory streams, respectively. PMID:24475030

Segregation and integration of auditory streams when listening to multi-part music.

PubMed

Ragert, Marie; Fairhurst, Merle T; Keller, Peter E

2014-01-01

In our daily lives, auditory stream segregation allows us to differentiate concurrent sound sources and to make sense of the scene we are experiencing. However, a combination of segregation and the concurrent integration of auditory streams is necessary in order to analyze the relationship between streams and thus perceive a coherent auditory scene. The present functional magnetic resonance imaging study investigates the relative role and neural underpinnings of these listening strategies in multi-part musical stimuli. We compare a real human performance of a piano duet and a synthetic stimulus of the same duet in a prioritized integrative attention paradigm that required the simultaneous segregation and integration of auditory streams. In so doing, we manipulate the degree to which the attended part of the duet led either structurally (attend melody vs. attend accompaniment) or temporally (asynchronies vs. no asynchronies between parts), and thus the relative contributions of integration and segregation used to make an assessment of the leader-follower relationship. We show that perceptually the relationship between parts is biased towards the conventional structural hierarchy in western music in which the melody generally dominates (leads) the accompaniment. Moreover, the assessment varies as a function of both cognitive load, as shown through difficulty ratings and the interaction of the temporal and the structural relationship factors. Neurally, we see that the temporal relationship between parts, as one important cue for stream segregation, revealed distinct neural activity in the planum temporale. By contrast, integration used when listening to both the temporally separated performance stimulus and the temporally fused synthetic stimulus resulted in activation of the intraparietal sulcus. These results support the hypothesis that the planum temporale and IPS are key structures underlying the mechanisms of segregation and integration of auditory streams, respectively.

Antioxidant activity of taxifolin: an activity-structure relationship.

PubMed

Topal, Fevzi; Nar, Meryem; Gocer, Hulya; Kalin, Pınar; Kocyigit, Umit M; Gülçin, İlhami; Alwasel, Saleh H

2016-08-01

Taxifolin is a kind of flavanonol, whose biological ability. The objectives of this study were to investigate the antioxidants and antiradical activities of taxifolin by using different in vitro bioanalytical antioxidant methods including DMPD√(+), ABTS√(+), [Formula: see text], and DPPH√-scavenging effects, the total antioxidant influence, reducing capabilities, and Fe(2+)-chelating activities. Taxifolin demonstrated 81.02% inhibition of linoleic acid emulsion peroxidation at 30 µg/mL concentration. At the same concentration, standard antioxidants including trolox, α-tocopherol, BHT, and BHA exhibited inhibitions of linoleic acid emulsion as 88.57, 73.88, 94.29, and 90.12%, respectively. Also, taxifolin exhibited effective DMPD√(+), ABTS√(+), [Formula: see text], and DPPH√-scavenging effects, reducing capabilities, and Fe(2+)-chelating effects. The results obtained from this study clearly showed that taxifolin had marked antioxidant, reducing ability, radical scavenging and metal-chelating activities. Also, this study exhibits a scientific shore for the significant antioxidant activity of taxifolin and its structure-activity insight.

Structural and functional social network attributes moderate the association of self-rated health with mental health in midlife and older adults.

PubMed

Windsor, Tim D; Rioseco, Pilar; Fiori, Katherine L; Curtis, Rachel G; Booth, Heather

2016-01-01

Social relationships are multifaceted, and different social network components can operate via different processes to influence well-being. This study examined associations of social network structure and relationship quality (positive and negative social exchanges) with mental health in midlife and older adults. The focus was on both direct associations of network structure and relationship quality with mental health, and whether these social network attributes moderated the association of self-rated health (SRH) with mental health. Analyses were based on survey data provided by 2001 (Mean age = 65, SD = 8.07) midlife and older adults. We used Latent Class Analysis (LCA) to classify participants into network types based on network structure (partner status, network size, contact frequency, and activity engagement), and used continuous measures of positive and negative social exchanges to operationalize relationship quality. Regression analysis was used to test moderation. LCA revealed network types generally consistent with those reported in previous studies. Participants in more diverse networks reported better mental health than those categorized into a restricted network type after adjustment for age, sex, education, and employment status. Analysis of moderation indicated that those with poorer SRH were less likely to report poorer mental health if they were classified into more diverse networks. A similar moderation effect was also evident for positive exchanges. The findings suggest that both quantity and quality of social relationships can play a role in buffering against the negative implications of physical health decline for mental health.

Family Influences on Adolescents’ Birth Control and Condom Use, Likelihood of Sexually Transmitted Infections

ERIC Educational Resources Information Center

Kao, Tsui-Sui Annie; Manczak, Melissa

2013-01-01

This study explored the relationships among personal factors, family structure and family function, adolescents’ self-efficacy for safe sex, and sexual behaviors among sexually active adolescents. A subset sample from the first three waves of the National Longitudinal Study of Adolescent Health (Add Health) was selected for this exploratory…

Relationships between species feeding traits and environmental conditions in fish communities: a three-matrix approach.

PubMed

Brind'Amour, Anik; Boisclair, Daniel; Dray, Stéphane; Legendre, Pierre

2011-03-01

Understanding the relationships between species biological traits and the environment is crucial to predicting the effect of habitat perturbations on fish communities. It is also an essential step in the assessment of the functional diversity. Using two complementary three-matrix approaches (fourth-corner and RLQ analyses), we tested the hypothesis that feeding-oriented traits determine the spatial distributions of littoral fish species by assessing the relationship between fish spatial distributions, fish species traits, and habitat characteristics in two Laurentian Shield lakes. Significant associations between the feeding-oriented traits and the environmental characteristics suggested that fish communities in small lakes (displaying low species richness) can be spatially structured. Three groups of traits, mainly categorized by the species spatial and temporal feeding activity, were identified. The water column may be divided in two sections, each of them corresponding to a group of traits related to the vertical distribution of the prey coupled with the position of the mouth. Lake areas of low structural complexity were inhabited by functional assemblages dominated by surface feeders while structurally more complex areas were occupied by mid-water and benthic feeders. A third group referring to the time of feeding activity was observed. Our work could serve as a guideline study to evaluate species traits x environment associations at multiple spatial scales. Our results indicate that three-matrix statistical approaches are powerful tools that can be used to study such relationships. These recent statistical approaches open up new research directions such as the study of spatially based biological functions in lakes. They also provide new analytical tools for determining, for example, the potential size of freshwater protected areas.

Selective kappa-opioid agonists: synthesis and structure-activity relationships of piperidines incorporating on oxo-containing acyl group.

PubMed

Giardina, G; Clarke, G D; Dondio, G; Petrone, G; Sbacchi, M; Vecchietti, V

1994-10-14

This study describes the synthesis and the structure-activity relationships (SARs) of the (S)-(-)-enantiomers of a novel class of 2-(aminomethyl)piperidine derivatives, using kappa-opioid binding affinity and antinociceptive potency as the indices of biological activity. Compounds incorporating the 1-tetralon-6-ylacetyl residue (30 and 34-45) demonstrated an in vivo antinociceptive activity greater than predicted on the basis of their kappa-binding affinities. In particular, (2S)-2-[(dimethylamino)methyl]-1-[(5,6,7,8-tetrahydro-5-oxo-2- naphthyl)acetyl]piperidine (34) was found to have a potency similar to spiradoline in animal models of antinociception after subcutaneous administration, with ED50s of 0.47 and 0.73 mumol/kg in the mouse and in the rat abdominal constriction tests, respectively. Further in vivo studies in mice and/or rats revealed that compound 34, compared to other selective kappa-agonists, has a reduced propensity to cause a number of kappa-related side effects, including locomotor impairment/sedation and diuresis, at antinociceptive doses. For example, it has an ED50 of 26.5 mumol/kg sc in the rat rotarod model, exhibiting a ratio of locomotor impairment/sedation vs analgesia of 36. Possible reasons for this differential activity and its clinical consequence are discussed.

Morphological relationships in the chromospheric H-alpha fine structure

NASA Technical Reports Server (NTRS)

Foukal, P.

1971-01-01

A continuous relationship is proposed between the basic elements of the dark fine structure of the quiet and active chromosphere. A progression from chromospheric bushes to fibrils, then to chromospheric threads and active region filaments, and finally to diffuse quiescent filaments, is described. It is shown that the horizontal component of the field on opposite sides of an active region quiescent filament can be in the same direction and closely parallel to the filament axis. Consequently, it is unnecessary to postulate twisted or otherwise complex field configurations to reconcile the support mechanism of filaments with the observed motion along their axis.

Pedagogical Beliefs, Activity Choice and Structure, and Adult-Child Interaction in Nursery Classrooms

ERIC Educational Resources Information Center

Blay, Josepha A.; Ireson, Judith

2009-01-01

A qualitative analysis of four cooking activities undertaken in two nursery classes reveals relationships between the adults' pedagogical beliefs, the choice and structuring of activities, and the nature of adult-child participation. Four adults each planned and carried out separately, one cooking activity of their choice with a small group of…

Computational & experimental evaluation of the structure/activity relationship of β-carbolines as DYRK1A inhibitors.

PubMed

Drung, Binia; Scholz, Christoph; Barbosa, Valéria A; Nazari, Azadeh; Sarragiotto, Maria H; Schmidt, Boris

2014-10-15

DYRK1A has been associated with Down's syndrome and neurodegenerative diseases, therefore it is an important target for novel pharmacological interventions. We combined a ligand-based pharmacophore design with a structure-based protein/ligand docking using the software MOE in order to evaluate the underlying structure/activity relationship. Based on this knowledge we synthesized several novel β-carboline derivatives to validate the theoretical model. Furthermore we identified a modified lead structure as a potent DYRK1A inhibitor (IC50=130 nM) with significant selectivity against MAO-A, DYRK2, DYRK3, DYRK4 & CLK2. Copyright © 2014 Elsevier Ltd. All rights reserved.

Abnormalities of thalamic activation and cognition in schizophrenia.

PubMed

Andrews, Jessica; Wang, Lei; Csernansky, John G; Gado, Mokhtar H; Barch, Deanna M

2006-03-01

Functional and structural magnetic resonance imaging (MRI) was used to investigate relationships among structure, functional activation, and cognitive deficits related to the thalamus in individuals with schizophrenia and healthy comparison subjects. Thirty-six schizophrenia subjects and 28 healthy comparison subjects matched by age, gender, race, and parental socioeconomic status underwent structural and functional MRI while performing a series of memory tasks, including an N-back task (working memory), intentional memorization of a series of pictures or words (episodic encoding), and a yes/no recognition task. Functional activation magnitudes in seven regions of interest within the thalamic complex, as defined by anatomical and functional criteria, were computed for each group. Participants with schizophrenia exhibited decreased activation within the whole thalamus, the anterior nuclei, and the medial dorsal nucleus. These nuclei overlap with subregions of the thalamic surface that the authors previously reported to exhibit morphological abnormalities in schizophrenia. However, there were no significant correlations between specific dimensions of thalamic shape variation (i.e., eigenvectors) and the activation patterns within thalamic regions of interest. Better performance on the working memory task among individuals with schizophrenia was significantly associated with increased activation in the anterior nuclei, the centromedian nucleus, the pulvinar, and the ventrolateral nuclei. These results suggest that there are limited relationships between morphological and functional abnormalities of the thalamus in schizophrenia subjects and highlight the importance of investigating relationships between brain structure and function.

Interaction of phenolic acids and their derivatives with human serum albumin: Structure-affinity relationships and effects on antioxidant activity.

PubMed

Zhang, Yunyue; Wu, Simin; Qin, Yinghui; Liu, Jiaxin; Liu, Jingwen; Wang, Qingyu; Ren, Fazheng; Zhang, Hao

2018-02-01

In this study, 111 phenolic acids and their derivatives were chosen to investigate their structure-affinity relationships when binding to human serum albumin (HSA), and effects on their antioxidant activity. A comprehensive mathematical model was employed to calculate the binding constants, using a fluorescence quenching method, and this was corrected for the inner-filter effect to improve accuracy. We found that a hydroxy group at the 2-position of the benzene ring exerted a positive effect on the affinities, while a 4-hydroxy substituent had a negative influence. Both methylation of the hydroxy groups and replacing the hydroxy groups with methyl groups at the 3- and 4-positions of the benzene ring enhanced the binding affinities. Hydrophobic force and hydrogen bonding were binding forces for the phenolic acids, and their methyl esters, respectively. The antioxidant activity of the HSA-phenolic acid interaction compounds was higher than that of the phenolic acids alone. Copyright © 2017. Published by Elsevier Ltd.

Antiproliferative terpenoids from almond hulls (Prunus dulcis): identification and structure-activity relationships.

PubMed

Amico, Vincenzo; Barresi, Vincenza; Condorelli, Daniele; Spatafora, Carmela; Tringali, Corrado

2006-02-08

Bioassay-guided fractionation of the EtOAc crude extract from Sicilian almond hulls, a waste material from Prunus dulcis crop, allowed identification of 10 constituents, isolated as pure compounds (1-5, 7, and 10) or unseparable mixtures (5 + 6 and 8 + 9). All compounds were subjected to spectroscopic analysis and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide bioassay on MCF-7 human breast cancer cells. In addition to the main components oleanolic (1), ursolic (2), and betulinic (3) acids, the 2-hydroxy analogues alphitolic (4), corosolic (5), and maslinic (6) acids, as well as the related aldehydes, namely, betulinic (7), oleanolic (8), and ursolic (9), were identified. From a more polar fraction, the beta-sitosterol 3-O-glucoside (10) was also identified. A sample of commercially available betulin (11) was also included in bioassays as further support to a structure-activity relationship study. Betulinic acid showed antiproliferative activity toward MCF-7 cells (GI50 = 0.27 microM), higher than the anticancer drug 5-fluorouracil.

Highly Reactive, General and Long-Lived Catalysts for Palladium-Catalyzed Amination of Heteroaryl and Aryl Chlorides, Bromides and Iodides: Scope and Structure-Activity Relationships

PubMed Central

Shen, Qilong; Ogata, Tokutaro; Hartwig, John F.

2010-01-01

We describe a systematic study of the scope and relationship between ligand structure and activity for a highly efficient and selective class of catalysts for the amination of heteroaryl and aryl chlorides, bromides and iodides containing sterically hindered chelating alkylphosphines. In the presence of this catalyst, aryl and heteroaryl chlorides, bromides and iodides react with many primary amines in high yields with part-per-million quantities of palladium precursor and ligand. Many reactions of primary amines with both heteroaryl and aryl chlorides, bromides and iodides occur to completion with 0.0005-0.05 mol % catalysts. A comparison of the reactivity of this catalyst for coupling of primary amines at these loadings is made with catalysts generated from hindered monophosphines and carbenes, and these data illustrate the benefits of chelation. Thus, these complexes constitute a fourth-generation catalyst for the amination of aryl halides, whose activity complements catalysts based on monophosphines and carbenes. PMID:18444639

Mathematical modeling of tetrahydroimidazole benzodiazepine-1-one derivatives as an anti HIV agent

NASA Astrophysics Data System (ADS)

Ojha, Lokendra Kumar

2017-07-01

The goal of the present work is the study of drug receptor interaction via QSAR (Quantitative Structure-Activity Relationship) analysis for 89 set of TIBO (Tetrahydroimidazole Benzodiazepine-1-one) derivatives. MLR (Multiple Linear Regression) method is utilized to generate predictive models of quantitative structure-activity relationships between a set of molecular descriptors and biological activity (IC50). The best QSAR model was selected having a correlation coefficient (r) of 0.9299 and Standard Error of Estimation (SEE) of 0.5022, Fisher Ratio (F) of 159.822 and Quality factor (Q) of 1.852. This model is statistically significant and strongly favours the substitution of sulphur atom, IS i.e. indicator parameter for -Z position of the TIBO derivatives. Two other parameter logP (octanol-water partition coefficient) and SAG (Surface Area Grid) also played a vital role in the generation of best QSAR model. All three descriptor shows very good stability towards data variation in leave-one-out (LOO).

Design, synthesis and structure-activity relationship study of wollamide B; a new potential anti TB agent

PubMed Central

Laqua, Katja; Walkowska, Anna Maria; Cunningham, Fraser; Martinez-Martinez, Maria Santos; Cuevas-Zurita, Juan Carlos; Ballell-Pages, Lluís; Imming, Peter

2017-01-01

Wollamide B is a cationic antimycobacterial cyclohexapeptide that exhibits activity against Mycobacterium bovis (M. bovis) (IC50 of 3.1 μM). Aiming to define its structural activity relationship (SAR), optimizing potency and pharmacokinetic properties, libraries of analogues were synthesized following a standard Fmoc-based solid phase peptide synthesis approach. The antimycobacterial activities of wollamide B and all the synthesized analogues were tested against Mycobacterium tuberculosis (Mtb) H37Rv. Parallely, in vitro drug metabolism and pharmacokinetic (ADME) profiling was done for the synthesized compounds to evaluate their drug likeness. Among the 25 synthesized wollamides five of them showed potent activities with MICs ≤ 3.1 μM and found to be nontoxic against human HepG2 cells up to 100 μM. The results of the in vitro ADME profiling revealed the remarkable plasma stability and very good aqueous solubility of the class in general while the metabolic stability was found to be moderate to low. Of particular note, compounds 7c (MIC = 1.1 μM) and 13c (0.6 μM) that exhibited good balance of antimycobacterial activity vs. optimal pharmacokinetic properties could be used as a new lead for further development. PMID:28423019

Identification of PGC-1α activating constituents in Zingiberaceous crude drugs.

PubMed

Nishidono, Yuto; Fujita, Takashi; Kawanami, Akira; Nishizawa, Mikio; Tanaka, Ken

2017-10-01

The activity of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) as an index of thermogenesis induced by four Indonesian Zingiberaceous crude drugs, Boesenbergia rotunda, Curcuma longa, Kaempferia galanga, Zingiber montanum, was examined, and GC-MS analyses of extracts of these drugs were performed. The results showed that activation of PGC-1α by K. galanga was high, whereas no activation was shown for the other drugs. Ethyl p-methoxycinnamate and ethyl cinnamate were identified as the PGC-1α activating compounds of K. galanga. Furthermore, study on the structure-activity relationship revealed that ethyl p-methoxycinnamate has the strongest activity among the cinnamic acid derivatives. This suggests that the ester structure and the methoxy group are important factors responsible for the PGC-1α activity. Copyright © 2017 Elsevier B.V. All rights reserved.

Comparative Bioinformatic Analysis of Active Site Structures in Evolutionarily Remote Homologues of α,β-Hydrolase Superfamily Enzymes.

PubMed

Suplatov, D A; Arzhanik, V K; Svedas, V K

2011-01-01

Comparative bioinformatic analysis is the cornerstone of the study of enzymes' structure-function relationship. However, numerous enzymes that derive from a common ancestor and have undergone substantial functional alterations during natural selection appear not to have a sequence similarity acceptable for a statistically reliable comparative analysis. At the same time, their active site structures, in general, can be conserved, while other parts may largely differ. Therefore, it sounds both plausible and appealing to implement a comparative analysis of the most functionally important structural elements - the active site structures; that is, the amino acid residues involved in substrate binding and the catalytic mechanism. A computer algorithm has been developed to create a library of enzyme active site structures based on the use of the PDB database, together with programs of structural analysis and identification of functionally important amino acid residues and cavities in the enzyme structure. The proposed methodology has been used to compare some α,β-hydrolase superfamily enzymes. The insight has revealed a high structural similarity of catalytic site areas, including the conservative organization of a catalytic triad and oxyanion hole residues, despite the wide functional diversity among the remote homologues compared. The methodology can be used to compare the structural organization of the catalytic and substrate binding sites of various classes of enzymes, as well as study enzymes' evolution and to create of a databank of enzyme active site structures.

Self-Efficacy, Depression, and Self-Care Activities in Adult Jordanians with Type 2 Diabetes: The Role of Illness Perception.

PubMed

Al-Amer, Rasmieh; Ramjan, Lucie; Glew, Paul; Randall, Sue; Salamonson, Yenna

2016-10-01

Diabetes mellitus is reaching epidemic levels worldwide. In a developing country like Jordan, type 2 diabetes mellitus (T2DM) has reached a prevalence rate of 17.1%. This cross-sectional study examined the relationship between self-care activities and: illness perception, depression, social support, religiosity and spiritual coping, and self-efficacy among patients with T2DM. A random sample of 220 patients with T2DM, who attended Jordan University Hospital in Jordan were enrolled. The data were collected through a structured interview and the medical files. The instruments consisted of a sociodemographic and clinical standardised questionnaires: Brief Illness Perception Questionnaire, Patients' Health Questionnaire-9; ENRICH Social Support Instrument; Religious and Spiritual Coping Subscale; Diabetes Management Self-Efficacy Scale; and Summary of Diabetes Self-Care Activities. Bivariate analysis investigated the relationship between variables. Structure Equation Modelling (SEM) was performed to test the proposed conceptual model. The study found that approximately 70% of the respondents suffered some form of depressive symptoms. The SEM showed a direct relationship between self-efficacy and self-care activities (β = 0.40; p < 0.001). Depression was indirectly related to self-care activities through self-efficacy (β = -0.20; p = 0.003); nevertheless, it was directly related to perception of: treatment control, consequences, and emotional representations. Overall, the sequence between illness perception and self-efficacy was mediated by depression. Strategies to promote self-efficacy and illness perception are vital in customising a diabetes health plan to meet Arabic cultural expectations.

Recent Advances in Marine Algae Polysaccharides: Isolation, Structure, and Activities.

PubMed

Xu, Shu-Ying; Huang, Xuesong; Cheong, Kit-Leong

2017-12-13

Marine algae have attracted a great deal of interest as excellent sources of nutrients. Polysaccharides are the main components in marine algae, hence a great deal of attention has been directed at isolation and characterization of marine algae polysaccharides because of their numerous health benefits. In this review, extraction and purification approaches and chemico-physical properties of marine algae polysaccharides (MAPs) are summarized. The biological activities, which include immunomodulatory, antitumor, antiviral, antioxidant, and hypolipidemic, are also discussed. Additionally, structure-function relationships are analyzed and summarized. MAPs' biological activities are closely correlated with their monosaccharide composition, molecular weights, linkage types, and chain conformation. In order to promote further exploitation and utilization of polysaccharides from marine algae for functional food and pharmaceutical areas, high efficiency, and low-cost polysaccharide extraction and purification methods, quality control, structure-function activity relationships, and specific mechanisms of MAPs activation need to be extensively investigated.

Separation of Oligosaccharides from Lotus Seeds via Medium-pressure Liquid Chromatography Coupled with ELSD and DAD

NASA Astrophysics Data System (ADS)

Lu, Xu; Zheng, Zhichang; Miao, Song; Li, Huang; Guo, Zebin; Zhang, Yi; Zheng, Yafeng; Zheng, Baodong; Xiao, Jianbo

2017-03-01

Lotus seeds were identified by the Ministry of Public Health of China as both food and medicine. One general function of lotus seeds is to improve intestinal health. However, to date, studies evaluating the relationship between bioactive compounds in lotus seeds and the physiological activity of the intestine are limited. In the present study, by using medium pressure liquid chromatography coupled with evaporative light-scattering detector and diode-array detector, five oligosaccharides were isolated and their structures were further characterized by electrospray ionization-mass spectrometry and gas chromatography-mass spectrometry. In vitro testing determined that LOS3-1 and LOS4 elicited relatively good proliferative effects on Lactobacillus delbrueckii subsp. bulgaricus. These results indicated a structure-function relationship between the physiological activity of oligosaccharides in lotus seeds and the number of probiotics applied, thus providing room for improvement of this particular feature. Intestinal probiotics may potentially become a new effective drug target for the regulation of immunity.

Structure-Activity Relationships of 6- and 8-Gingerol Analogs as Anti-Biofilm Agents.

PubMed

Choi, Hyunsuk; Ham, So-Young; Cha, Eunji; Shin, Yujin; Kim, Han-Shin; Bang, Jeong Kyu; Son, Sang-Hyun; Park, Hee-Deung; Byun, Youngjoo

2017-12-14

Pseudomonas aeruginosa is a causative agent of chronic infections in immunocompromised patients. Disruption of quorum sensing circuits is an attractive strategy for treating diseases associated with P. aeruginosa infection. In this study, we designed and synthesized a series of gingerol analogs targeting LasR, a master regulator of quorum sensing networks in P. aeruginosa. Structure-activity relationship studies showed that a hydrogen-bonding interaction in the head section, stereochemistry and rotational rigidity in the middle section, and optimal alkyl chain length in the tail section are important factors for the enhancement of LasR-binding affinity and for the inhibition of biofilm formation. The most potent compound 41, an analog of (R)-8-gingerol with restricted rotation, showed stronger LasR-binding affinity and inhibition of biofilm formation than the known LasR antagonist (S)-6-gingerol. This new LasR antagonist can be used as an early lead compound for the development of anti-biofilm agents to treat P. aeruginosa infections.

Exploring the process-structure-function relationship of horseradish peroxidase through investigation of pH- and heat induced conformational changes

NASA Astrophysics Data System (ADS)

Stănciuc, Nicoleta; Aprodu, Iuliana; Ioniță, Elena; Bahrim, Gabriela; Râpeanu, Gabriela

2015-08-01

Given the importance of peroxidase as an indicator for the preservation of vegetables by heat treatment, the present study is focused on enzyme behavior under different pH and temperature conditions, in terms of process-structure-function relationships. Thus, the process-structure-function relationship of peroxidase was investigated by combining fluorescence spectroscopy, in silico prediction methods and inactivation kinetic studies. The fluorescence spectra indicated that at optimum pH value, the Trp117 residue is not located in the hydrophobic core of the protein. Significant blue- and red-shifts were obtained at different pH values, whereas the heat-treatment did not cause significant changes in Trp and Tyr environment. The ANS and quenching experiments demonstrated a more flexible conformation at lower pH and respectively at higher temperature. On the other hand molecular dynamics simulations at different temperatures highlighted that the secondary structure appeared better preserved against temperature, whereas the tertiary structure around the heme was more affected. Temperature dependent changes in the hydrogen bonding and ion paring involving amino acids from the heme-binding region (His170 and Asp247) might trigger miss-coordination of the heme iron atom by His170 residue and further enzyme activity loss.

The Biological Activities of Sesterterpenoid-Type Ophiobolins.

PubMed

Tian, Wei; Deng, Zixin; Hong, Kui

2017-07-18

Ophiobolins (Ophs) are a group of tricarbocyclic sesterterpenoids whose structures contain a tricyclic 5-8-5 carbotricyclic skeleton. Thus far, 49 natural Ophs have been reported and assigned into A-W subgroups in order of discovery. While these sesterterpenoids were first characterized as highly effective phytotoxins, later investigations demonstrated that they display a broad spectrum of biological and pharmacological characteristics such as phytotoxic, antimicrobial, nematocidal, cytotoxic, anti-influenza and inflammation-promoting activities. These bioactive molecules are promising drug candidates due to the developments of their anti-proliferative activities against a vast number of cancer cell lines, multidrug resistance (MDR) cells and cancer stem cells (CSCs). Despite numerous studies on the biological functions of Ophs, their pharmacological mechanism still requires further research. This review summarizes the chemical structures, sources, and biological activities of the oph family and discusses its mechanisms and structure-activity relationship to lay the foundation for the future developments and applications of these promising molecules.

[Identification of the cumulative eco-environment effect of coal-electricity integration based on interpretative structural model].

PubMed

Han, Lin Wei; Fu, Xiao; Yan, Yan; Wang, Chen Xing; Wu, Gang

2017-05-18

In order to determine the cumulative eco-environmental effect of coal-electricity integration, we selected 29 eco-environmental factors including different development and construction activities of coal-electricity integration, soil, water, atmospheric conditions, biology, landscape, and ecology. Literature survey, expert questionnaire and interview were conducted to analyze the interactive relationships between different factors. The structure and correlations between the eco-environmental factors influenced by coal-electricity integration activities were analyzed using interpretive structural modeling (ISM) and the cumulative eco-environment effect of development and construction activities was determined. A research and evaluation framework for the cumulative eco-environmental effect was introduced in addition to specific evaluation and management needs. The results of this study would provide a theoretical and technical basis for planning and management of coal-electricity integration development activities.

Combination Chemistry: Structure-Activity Relationships of Novel Psychoactive Cannabinoids.

PubMed

Wiley, Jenny L; Marusich, Julie A; Thomas, Brian F

2017-01-01

Originally developed as research tools for use in structure-activity relationship studies, synthetic cannabinoids contributed to significant scientific advances in the cannabinoid field. Unfortunately, a subset of these compounds was diverted for recreational use beginning in the early 2000s. As these compounds were banned, they were replaced with additional synthetic cannabinoids with increasingly diverse chemical structures. This chapter focuses on integration of recent results with those covered in previous reviews. Whereas most of the early compounds were derived from the prototypic naphthoylindole JWH-018, currently popular synthetic cannabinoids include tetramethylcyclopropyl ketones and indazole-derived cannabinoids (e.g., AB-PINACA, AB-CHMINACA). Despite their structural differences, psychoactive synthetic cannabinoids bind with high affinity to CB 1 receptors in the brain and, when tested, have been shown to activate these receptors and to produce a characteristic profile of effects, including suppression of locomotor activity, antinociception, hypothermia, and catalepsy, as well as Δ 9 -tetrahydrocannabinol (THC)-like discriminative stimulus effects in mice. When they have been tested, synthetic cannabinoids are often found to be more efficacious at activation of the CB 1 receptor and more potent in vivo. Further, their chemical alteration by thermolysis during use and their uncertain stability and purity may result in exposure to degradants that differ from the parent compound contained in the original product. Consequently, while their intoxicant effects may be similar to those of THC, use of synthetic cannabinoids may be accompanied by unpredicted, and sometimes harmful, effects.

Parent-Child Relations and Peer Associations as Mediators of the Family Structure--Substance Use Relationship

ERIC Educational Resources Information Center

Crawford, Lizabeth A.; Novak, Katherine B.

2008-01-01

Using data from the National Education Longitudinal Survey of 1988, the authors assess the extent to which adolescents' levels of parental attachment and opportunities for participating in delinquent activities mediate the family structure--substance use relationship. A series of hierarchical regressions supported the hypotheses that high levels…

Quantitative structure-activity relationship modeling on in vitro endocrine effects and metabolic stability involving 26 selected brominated flame retardants.

PubMed

Harju, Mikael; Hamers, Timo; Kamstra, Jorke H; Sonneveld, Edwin; Boon, Jan P; Tysklind, Mats; Andersson, Patrik L

2007-04-01

In this work, quantitative structure-activity relationships (QSARs) were developed to aid human and environmental risk assessment processes for brominated flame retardants (BFRs). Brominated flame retardants, such as the high-production-volume chemicals polybrominated diphenyl ethers (PBDEs), tetrabromobisphenol A, and hexabromocyclododecane, have been identified as potential endocrine disruptors. Quantitative structure-activity relationship models were built based on the in vitro potencies of 26 selected BFRs. The in vitro assays included interactions with, for example, androgen, progesterone, estrogen, and dioxin (aryl hydrocarbon) receptor, plus competition with thyroxine for its plasma carrier protein (transthyretin), inhibition of estradiol sulfation via sulfotransferase, and finally, rate of metabolization. The QSAR modeling, a number of physicochemical parameters were calculated describing the electronic, lipophilic, and structural characteristics of the molecules. These include frontier molecular orbitals, molecular charges, polarities, log octanol/water partitioning coefficient, and two- and three-dimensional molecularproperties. Experimental properties were included and measured for PBDEs, such as their individual ultraviolet spectra (200-320 nm) and retention times on three different high-performance liquid chromatography columns and one nonpolar gas chromatography column. Quantitative structure-activity relationship models based on androgen antagonism and metabolic degradation rates generally gave similar results, suggesting that lower-brominated PBDEs with bromine substitutions in ortho positions and bromine-free meta- and para positions had the highest potencies and metabolic degradation rates. Predictions made for the constituents of the technical flame retardant Bromkal 70-5DE found BDE 17 to be a potent androgen antagonist and BDE 66, which is a relevant PBDE in environmental samples, to be only a weak antagonist.

Development of Novel p16INK4a Mimetics as Anticancer Therapy

DTIC Science & Technology

2015-10-01

peptide (or substituted peptide) or the crystal structure of the relevant sequence from p16INK4 ( PDB 1BI7) was used as the starting structure . Model...small peptides that interact with CDK4/6. The specific aims are as follows. (1) Determine structure -function relationships of overlapping peptides...Determine structure -function relationships of overlapping peptides derived from p16 INK4a that inhibit the activity of CDK4/6 and identify stabilized

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.

Structural diversity in the dandelion (Taraxacum officinale) polyphenol oxidase family results in different responses to model substrates.

PubMed

Dirks-Hofmeister, Mareike E; Singh, Ratna; Leufken, Christine M; Inlow, Jennifer K; Moerschbacher, Bruno M

2014-01-01

Polyphenol oxidases (PPOs) are ubiquitous type-3 copper enzymes that catalyze the oxygen-dependent conversion of o-diphenols to the corresponding quinones. In most plants, PPOs are present as multiple isoenzymes that probably serve distinct functions, although the precise relationship between sequence, structure and function has not been addressed in detail. We therefore compared the characteristics and activities of recombinant dandelion PPOs to gain insight into the structure-function relationships within the plant PPO family. Phylogenetic analysis resolved the 11 isoenzymes of dandelion into two evolutionary groups. More detailed in silico and in vitro analyses of four representative PPOs covering both phylogenetic groups were performed. Molecular modeling and docking predicted differences in enzyme-substrate interactions, providing a structure-based explanation for grouping. One amino acid side chain positioned at the entrance to the active site (position HB2+1) potentially acts as a "selector" for substrate binding. In vitro activity measurements with the recombinant, purified enzymes also revealed group-specific differences in kinetic parameters when the selected PPOs were presented with five model substrates. The combination of our enzyme kinetic measurements and the in silico docking studies therefore indicate that the physiological functions of individual PPOs might be defined by their specific interactions with different natural substrates.

Ginsenosides from American ginseng: Chemical and pharmacological diversity

PubMed Central

Qi, Lian-Wen; Wang, Chong-Zhi; Yuan, Chun-Su

2011-01-01

Ginseng occupies a prominent position in the list of best-selling natural products in the world. Compared to the long history of use and widespread research on Asian ginseng, the study of American ginseng is relatively limited. In the past decade, some promising advances have been achieved in understanding the chemistry, pharmacology and structure-function relationship of American ginseng. To date, there is no systematic review of American ginseng. In this review, we present the different structures of the ginsenosides in American ginseng, including naturally occurring compounds and those resulting from steaming or biotransformation. Preclinical and clinical studies published in the past decade will also be discussed. We highlight the chemical and pharmacological diversity and potential structural-activity relationship of ginsenosides. Our hope is that this article is a useful reference to chemists and biologists researching American ginseng, and will open the door to novel agents in drug discovery. PMID:21396670

Structure-Activity Relationship Studies on Derivatives of Eudesmanolides from Inula Helenium as Toxicants against Aedes Aegypti Larvae and Adults

DTIC Science & Technology

2010-01-01

flavonoids , sesquiterpenoids, and triterpenoids, among others, were CHEMISTRY & BIODIVERSITY – Vol. 7 (2010)1682 Table 1. Larvicidal Activities of Various...Gainesville, FL 32608, USA c) Department of Chemistry , Louisiana State University, Baton Rouge, Louisiana 70803, USA AnAedes aegypti larval toxicity...bioassay was performed on compounds representing many classes of natural compounds including polyacetylenes, phytosterols, flavonoids

Texaphyrins: Tumor Localizing Redox Active Expanded Porphyrins

PubMed Central

Arambula, Jonathan F.; Preihs, Christian; Borthwick, Derric; Magda, Darren; Sessler, Jonathan L.

2011-01-01

Texaphyrins, a class of tumor selective expanded porphyrins capable of coordinating large metals, have been found to act as redox mediators within biological systems. This review summarizes studies involving their experimentaluse in cancer chemotherapy. Mechanistic insights involving their presumed mode of action are also described, as well as certain structure activity relationships. Finally, newer texaphyrin-based applications associated with targeted drug delivery are presented. PMID:21355841

Structure-activity relationships of C6-uridine derivatives targeting plasmodia orotidine monophosphate decarboxylase.

PubMed

Bello, Angelica M; Poduch, Ewa; Liu, Yan; Wei, Lianhu; Crandall, Ian; Wang, Xiaoyang; Dyanand, Christopher; Kain, Kevin C; Pai, Emil F; Kotra, Lakshmi P

2008-02-14

Malaria, caused by Plasmodia parasites, has re-emerged as a major problem, imposing its fatal effects on human health, especially due to multidrug resistance. In Plasmodia, orotidine 5'-monophosphate decarboxylase (ODCase) is an essential enzyme for the de novo synthesis of uridine 5'-monophosphate. Impairing ODCase in these pathogens is a promising strategy to develop novel classes of therapeutics. Encouraged by our recent discovery that 6-iodo uridine is a potent inhibitor of P. falciparum, we investigated the structure-activity relationships of various C6 derivatives of UMP. 6-Cyano, 6-azido, 6-amino, 6-methyl, 6- N-methylamino, and 6- N, N-dimethylamino derivatives of uridine were evaluated against P. falciparum. The mononucleotides of 6-cyano, 6-azido, 6-amino, and 6-methyl uridine derivatives were studied as inhibitors of plasmodial ODCase. 6-Azidouridine 5'-monophosphate is a potent covalent inhibitor of P. falciparum ODCase. 6-Methyluridine exhibited weak antimalarial activity against P. falciparum 3D7 isolate. 6- N-Methylamino and 6- N, N-dimethylamino uridine derivatives exhibited moderate antimalarial activities.

New model framework and structure and the commonality evaluation model. [concerning unmanned spacecraft projects

NASA Technical Reports Server (NTRS)

1977-01-01

The development of a framework and structure for shuttle era unmanned spacecraft projects and the development of a commonality evaluation model is documented. The methodology developed for model utilization in performing cost trades and comparative evaluations for commonality studies is discussed. The model framework consists of categories of activities associated with the spacecraft system's development process. The model structure describes the physical elements to be treated as separate identifiable entities. Cost estimating relationships for subsystem and program-level components were calculated.

Design, synthesis and structure-activity relationship evaluation of novel LpxC inhibitors as Gram-negative antibacterial agents.

PubMed

Ding, Shi; Dai, Rui-Yang; Wang, Wen-Ke; Cao, Qiao; Lan, Le-Fu; Zhou, Xian-Li; Yang, Yu-She

2018-01-15

LpxC inhibitors are new-type antibacterial agents developed in the last twenty years, mainly against Gram-negative bacteria infections. To develop novel LpxC inhibitors with good antibacterial activities and biological metabolism, we summarized the basic skeleton of reported LpxC inhibitors, designed and synthesized several series of compounds and tested their antibacterial activities against Escherichial coli and Pseudomonas aeruginosa in vitro. Structure-activity relationships have been discussed in this article. The metabolism stability of YDL-2, YDL-5, YDL-8, YDL-14, YDL-20-YDL-23 have been evaluated in liver microsomes, which indicated that the 2-amino isopropyl group may be a preferred structure than the 2-hydroxy ethyl group in the design of LpxC inhibitors. Copyright © 2017 Elsevier Ltd. All rights reserved.

Relationship between smartphone addiction and physical activity in Chinese international students in Korea

PubMed Central

Kim, Sung-Eun; Kim, Jin-Woo; Jee, Yong-Seok

2015-01-01

Background and Aims Excessive usage of smartphones may induce social problems, such as depression and impairment of social and emotional functioning. Moreover, its usage can impede physical activity, but the relationship between smartphone addiction and physical activity is obscure. Therefore, we examined the relationship and the impact of excessive smartphone use on physical activity. Methods This study collected data through the structured questionnaire consisting of general characteristics, the number and hours of smartphone usage, and the Smartphone Addiction Proneness Scale (SAPS) from 110 Chinese international students in Korea. The body composition and physical activity, such as the total daily number of steps and consumed calories, were measured. Results In this study, high-risk smartphone users showed less physical activity, such as the total number of steps taken and the average consumed calories per day. Moreover, their body composition, such as muscle mass and fat mass, was significantly different. Among these factors, the hours of smartphone use revealed the proportional relationship with smartphone addiction (β = 0.209, p = 0.026), while the average number of walking steps per day showed a significant reverse proportional tendency in participants with smartphone addiction (β = –0.883, p < 0.001). Conclusions Participants with smartphone addiction were less likely to walk for each day. Namely, smartphone addiction may negatively influence physical health by reducing the amount of physical activity, such as walking, resulting in an increase of fat mass and a decrease of muscle mass associated with adverse health consequences. PMID:26551911

Relationship between smartphone addiction and physical activity in Chinese international students in Korea.

PubMed

Kim, Sung-Eun; Kim, Jin-Woo; Jee, Yong-Seok

2015-09-01

Excessive usage of smartphones may induce social problems, such as depression and impairment of social and emotional functioning. Moreover, its usage can impede physical activity, but the relationship between smartphone addiction and physical activity is obscure. Therefore, we examined the relationship and the impact of excessive smartphone use on physical activity. This study collected data through the structured questionnaire consisting of general characteristics, the number and hours of smartphone usage, and the Smartphone Addiction Proneness Scale (SAPS) from 110 Chinese international students in Korea. The body composition and physical activity, such as the total daily number of steps and consumed calories, were measured. In this study, high-risk smartphone users showed less physical activity, such as the total number of steps taken and the average consumed calories per day. Moreover, their body composition, such as muscle mass and fat mass, was significantly different. Among these factors, the hours of smartphone use revealed the proportional relationship with smartphone addiction (β = 0.209, p = 0.026), while the average number of walking steps per day showed a significant reverse proportional tendency in participants with smartphone addiction (β = -0.883, p < 0.001). Participants with smartphone addiction were less likely to walk for each day. Namely, smartphone addiction may negatively influence physical health by reducing the amount of physical activity, such as walking, resulting in an increase of fat mass and a decrease of muscle mass associated with adverse health consequences.

The structure-AChE inhibitory activity relationships study in a series of pyridazine analogues.

PubMed

Saracoglu, M; Kandemirli, F

2009-07-01

The structure-activity relationships (SAR) are investigated by means of the Electronic-Topological Method (ETM) followed by the Neural Networks application (ETM-NN) for a class of anti-cholinesterase inhibitors (AChE, 53 molecules) being pyridazine derivatives. AChE activities of the series were measured in IC(50) units, and relative to the activity levels, the series was partitioned into classes of active and inactive compounds. Based on pharmacophores and antipharmacophores calculated by the ETM-software as sub-matrices containing important spatial and electronic characteristics, a system for the activity prognostication is developed. Input data for the ETM were taken as the results of conformational and quantum-mechanics calculations. To predict the activity, we used one of the most well known neural networks, namely, the feed-forward neural networks (FFNNs) trained with the back propagation algorithm. The supervised learning was performed using a variant of FFNN known as the Associative Neural Networks (ASNN). The result of the testing revealed that the high ETM's ability of predicting both activity and inactivity of potential AChE inhibitors. Analysis of HOMOs for the compounds containing Ph1 and APh1 has shown that atoms with the highest values of the atomic orbital coefficients are mainly those atoms that enter into the pharmacophores. Thus, the set of pharmacophores and antipharmacophores found as the result of this study forms a basis for a system of the anti-cholinesterase activity prediction.

The Lysozyme from Insect (Manduca sexta) is a Cold-Adapted Enzyme

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

Sotelo-Mundo,R.; Lopez-Zavala, A.; Garcia-Orozco, K.

Enzymatic activity is dependent on temperature, although some proteins have evolved to retain activity at low temperatures at the expense of stability. Cold adapted enzymes are present in a variety of organisms and there is ample interest in their structure-function relationships. Lysozyme (E.C. 3.2.1.17) is one of the most studied enzymes due to its antibacterial activity against Gram positive bacteria and is also a cold adapted protein. In this work the characterization of lysozyme from the insect Manduca sexta and its activity at low temperatures is presented. Both M. sexta lysozymes natural and recombinant showed a higher content of {alpha}-helixmore » secondary structure compared to that of hen egg white lysozyme and a higher specific enzymatic activity in the range of 5-30 {sup o}C. These results together with measured thermodynamic activation parameters support the designation of M. sexta lysozyme as a cold adapted enzyme. Therefore, the insect recombinant lysozyme is feasible as a model for structure-function studies for cold-adapted proteins.« less

An Extended Structure-Activity Relationship of Nondioxin-Like PCBs Evaluates and Supports Modeling Predictions and Identifies Picomolar Potency of PCB 202 Towards Ryanodine Receptors.

PubMed

Holland, Erika B; Feng, Wei; Zheng, Jing; Dong, Yao; Li, Xueshu; Lehmler, Hans-Joachim; Pessah, Isaac N

2017-01-01

Nondioxin-like polychlorinated biphenyls (NDL PCBs) activate ryanodine-sensitive Ca 2+  channels (RyRs) and this activation has been associated with neurotoxicity in exposed animals. RyR-active congeners follow a distinct structure-activity relationship and a quantitative structure-activity relationship (QSAR) predicts that a large number of PCBs likely activate the receptor, which requires validation. Additionally, previous structural based conclusions have been established using receptor ligand binding assays but the impact of varying PCB structures on ion channel gating behavior is not understood. We used [ 3 H]Ryanodine ([ 3 H]Ry) binding to assess the RyR-activity of 14 previously untested PCB congeners evaluating the predictability of the QSAR. Congeners determined to display widely varying potency were then assayed with single channel voltage clamp analysis to assess direct influences on channel gating kinetics. The RyR-activity of individual PCBs assessed in in vitro assays followed the general pattern predicted by the QSAR but binding and lipid bilayer experiments demonstrated higher potency than predicted. Of the 49 congeners tested to date, tetra-ortho PCB 202 was found to be the most potent RyR-active congener increasing channel open probability at 200 pM. Shifting meta-substitutions to the para-position resulted in a > 100-fold reduction in potency as seen with PCB 197. Non-ortho PCB 11 was found to lack activity at the receptor supporting a minimum mono-ortho substitution for PCB RyR activity. These findings expand and support previous SAR assessments; where out of the 49 congeners tested to date 42 activate the receptor demonstrating that the RyR is a sensitive and common target of PCBs. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Structure-Activity Relationship Study of Ionotropic Glutamate Receptor Antagonist (2S,3R)-3-(3-Carboxyphenyl)pyrrolidine-2-carboxylic Acid.

PubMed

Krogsgaard-Larsen, Niels; Storgaard, Morten; Møller, Charlotte; Demmer, Charles S; Hansen, Jeanette; Han, Liwei; Monrad, Rune N; Nielsen, Birgitte; Tapken, Daniel; Pickering, Darryl S; Kastrup, Jette S; Frydenvang, Karla; Bunch, Lennart

2015-08-13

Herein we describe the first structure-activity relationship study of the broad-range iGluR antagonist (2S,3R)-3-(3-carboxyphenyl)pyrrolidine-2-carboxylic acid (1) by exploring the pharmacological effect of substituents in the 4, 4', or 5' positions and the bioisosteric substitution of the distal carboxylic acid for a phosphonic acid moiety. Of particular interest is a hydroxyl group in the 4' position 2a which induced a preference in binding affinity for homomeric GluK3 over GluK1 (Ki = 0.87 and 4.8 μM, respectively). Two X-ray structures of ligand binding domains were obtained: 2e in GluA2-LBD and 2f in GluK1-LBD, both at 1.9 Å resolution. Compound 2e induces a D1-D2 domain opening in GluA2-LBD of 17.3-18.8° and 2f a domain opening in GluK1-LBD of 17.0-17.5° relative to the structures with glutamate. The pyrrolidine-2-carboxylate moiety of 2e and 2f shows a similar binding mode as kainate. The 3-carboxyphenyl ring of 2e and 2f forms contacts comparable to those of the distal carboxylate in kainate.

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.

Exploring moderators of the relationship between physical activity behaviors and television viewing in elementary school children.

PubMed

Smith, Nicole E I; Rhodes, Ryan E; Naylor, Patti-Jean; McKay, Heather A

2008-01-01

Previous research suggests that there is limited evidence to support a negative association between physical activity (PA) behaviors and television (TV) viewing time in children. The purpose of this study was to extend the research involving PA-TV viewing relationships and to explore potential moderators, including gender, ethnicity, weekday/ weekend behaviors, structured/unstructured activities, and seasonal variability. A 9-month longitudinal design, across one school year, with assessments every 3 months. Elementary schools in the Vancouver and Richmond districts of British Columbia, Canada. Subjects. Subjects (N = 344; 47% female) were 9- to 11-year-old children who participated in a school-based PA initiative from September 2003 to June 2004. Not applicable. Assessments of PA were measured using the Physical Activity Questionnaire for Children. TV viewing time and structured PA were measured using a self-report questionnaire. Basic descriptives, Pearson r bivariate correlations and moderated multiple regressions with mean centered variables. No significant interaction effects were found for any of the proposed moderators. Null bivariate correlations are supportive of findings in previous literature. Our results did not find support for PA-TV viewing relations, regardless of gender, ethnicity, structured PA, and seasonal variability. PA interventions aimed at modifying sedentary behaviors, such as TV viewing, may not be warranted.

Correlates of male cohabiting partner's involvement in child-rearing tasks in low-income urban Black stepfamilies.

PubMed

Forehand, Rex; Parent, Justin; Golub, Andrew; Reid, Megan

2014-06-01

Cohabitation is a family structure experienced by many Black children. This study examines the link between family relationships (child relationship with mother and the cohabiting partner; parent and cohabiting partner relationship) and involvement of biologically unrelated male cohabiting partners (MCP) in child rearing. The participants were 121 low-income urban Black families consisting of a single mother, MCP, and an adolescent (56% female, M age = 13.7). Assessments were conducted individually with mothers, MCPs, and adolescents via measures administered by interview. MCPs were involved in both domains of child rearing assessed (daily child-related tasks and setting limits) and those identified as coparents by the mother were more involved in child-rearing tasks than those not identified as coparents. Using structural equation modeling (SEM), the mother-MCP relationship (both support and conflict) and the adolescent-MCP relationship were related to MCP's involvement in both domains of child rearing. The findings indicate that MCPs are actively involved in child rearing and family relationship variables are associated with their involvement in these tasks. PsycINFO Database Record (c) 2014 APA, all rights reserved.

Sedentary Screen Time and Left Ventricular Structure and Function: the CARDIA Study

PubMed Central

Gibbs, Bethany Barone; Reis, Jared P.; Schelbert, Erik B.; Craft, Lynette L.; Sidney, Steve; Lima, Joao; Lewis, Cora E.

2013-01-01

Sedentary screen time (watching TV or using a computer) predicts cardiovascular outcomes independently from moderate and vigorous physical activity and could impact left ventricular structure and function through the adverse consequences of sedentary behavior. Purpose To determine whether sedentary screen time is associated with measures of left ventricular structure and function. Methods The Coronary Artery Risk Development in Young Adults (CARDIA) Study measured screen time by questionnaire and left ventricular structure and function by echocardiography in 2,854 black and white participants, aged 43–55 years, in 2010–2011. Generalized linear models evaluated cross-sectional trends for echocardiography measures across higher categories of screen time and adjusting for demographics, smoking, alcohol, and physical activity. Further models adjusted for potential intermediate factors (blood pressure, antihypertensive medication use, diabetes, and body mass index (BMI). Results The relationship between screen time and left ventricular mass(LVM) differed in blacks vs. whites. Among whites, higher screen time was associated with larger LVM (P<0.001), after adjustment for height, demographics, and lifestyle variables. Associations between screen time and LVM persisted when adjusting for blood pressure, antihypertensive medication use, and diabetes (P=0.008) but not with additional adjustment for BMI (P=0.503). Similar relationships were observed for screen time with LVM indexed to height2.7, relative wall thickness, and mass-to-volume ratio. Screen time was not associated with left ventricular structure among blacks or left ventricular function in either race group. Conclusions Sedentary screen time is associated with greater LVM in white adults and this relationship was largely explained by higher overall adiposity. The lack of association in blacks supports a potential qualitative difference in the cardiovascular consequences of sedentary screen-based behavior. PMID:23863618

Adult daughters providing post-stroke care to a parent: a qualitative study of the impact that role overload has on lifestyle, participation and family relationships.

PubMed

Bastawrous, Marina; Gignac, Monique A; Kapral, Moira K; Cameron, Jill I

2015-06-01

To qualitatively explore daughters' experiences with and response to holding multiple roles while providing post-stroke care to a parent. Qualitative study using a descriptive approach. Semi-structured interviewing was used. Interviews were recorded, transcribed and analyzed to develop themes. General community of a metropolitan city. Twenty-three adult daughters caring for a community-dwelling parent who had suffered a stroke. Not applicable. Not applicable. Role overload is a salient issue for daughter caregivers. This overload is best captured by the analogy of "juggling" multiple role demands and responsibilities. Two key themes suggest that role overload resulting from parent care affects daughters': 1) valued relationships (e.g. challenges develop in their relationship with children and partner); and 2) ability to participate in valued activities (e.g. reduced involvement in leisure activities and restricted employment). Future support efforts should help daughters manage the caregiving role in light of other responsibilities. This can mitigate overload-related strain in valued relationships and decreased participation in valued activities, thereby contributing to better health and well-being for daughter caregivers. © The Author(s) 2014.

Structural Basis for the Effective Myostatin Inhibition of the Mouse Myostatin Prodomain-Derived Minimum Peptide.

PubMed

Asari, Tomo; Takayama, Kentaro; Nakamura, Akari; Shimada, Takahiro; Taguchi, Akihiro; Hayashi, Yoshio

2017-01-12

Myostatin inhibition is one of the promising strategies for treating muscle atrophic disorders, including muscular dystrophy. It is well-known that the myostatin prodomain derived from the myostatin precursor acts as an inhibitor of mature myostatin. In our previous study, myostatin inhibitory minimum peptide 1 (WRQNTRYSRIEAIKIQILSKLRL-amide) was discovered from the mouse myostatin prodomain. In the present study, alanine scanning of 1 demonstrated that the key amino acid residues for the effective inhibitory activity are rodent-specific Tyr and C-terminal aliphatic residues, in addition to N-terminal Trp residue. Subsequently, we designed five Pro-substituted peptides and examined the relationship between secondary structure and inhibitory activity. As a result, we found that Pro-substitutions of Ala or Gln residues around the center of 1 significantly decreased both α-helicity and inhibitory activity. These results suggested that an α-helical structure possessing hydrophobic faces formed around the C-terminus is important for inhibitory activity.

Decoupling Activation of Heme Biosynthesis from Anaerobic Toxicity in a Molecule Active in Staphylococcus aureus.

PubMed

Dutter, Brendan F; Mike, Laura A; Reid, Paul R; Chong, Katherine M; Ramos-Hunter, Susan J; Skaar, Eric P; Sulikowski, Gary A

2016-05-20

Small molecules active in the pathogenic bacterium Staphylococcus aureus are valuable tools for the study of its basic biology and pathogenesis, and many molecules may provide leads for novel therapeutics. We have previously reported a small molecule, 1, which activates endogenous heme biosynthesis in S. aureus, leading to an accumulation of intracellular heme. In addition to this novel activity, 1 also exhibits toxicity towards S. aureus growing under fermentative conditions. To determine if these activities are linked and establish what features of the molecule are required for activity, we synthesized a library of analogs around the structure of 1 and screened them for activation of heme biosynthesis and anaerobic toxicity to investigate structure-activity relationships. The results of this analysis suggest that these activities are not linked. Furthermore, we have identified the structural features that promote each activity and have established two classes of molecules: activators of heme biosynthesis and inhibitors of anaerobic growth. These molecules will serve as useful probes for their respective activities without concern for the off target effects of the parent compound.

Membrane Phospholipid Augments Cytochrome P4501a Enzymatic Activity by Modulating Structural Conformation during Detoxification of Xenobiotics

PubMed Central

Ghosh, Manik C.; Ray, Arun K.

2013-01-01

Cytochrome P450 is a superfamily of membrane-bound hemoprotein that gets involved with the degradation of xenobiotics and internal metabolites. Accumulated body of evidence indicates that phospholipids play a crucial role in determining the enzymatic activity of cytochrome P450 in the microenvironment by modulating its structure during detoxification; however, the structure-function relationship of cytochrome P4501A, a family of enzymes responsible for degrading lipophilic aromatic hydrocarbons, is still not well defined. Inducibility of cytochrome P4501A in cultured catfish hepatocytes in response to carbofuran, a widely used pesticide around the world, was studied earlier in our laboratory. In this present investigation, we observed that treating catfish with carbofuran augmented total phospholipid in the liver. We examined the role of phospholipid on the of cytochrome P4501A-marker enzyme which is known as ethoxyresorufin-O-deethylase (EROD) in the context of structure and function. We purified the carbofuran-induced cytochrome P4501A protein from catfish liver. Subsequently, we examined the enzymatic activity of purified P4501A protein in the presence of phospholipid, and studied how the structure of purified protein was influenced in the phospholipid environment. Membrane phospholipid appeared to accelerate the enzymatic activity of EROD by changing its structural conformation and thus controlling the detoxification of xenobiotics. Our study revealed the missing link of how the cytochrome P450 restores its enzymatic activity by changing its structural conformation in the phospholipid microenvironment. PMID:23469105