Nonlinear dependence in comparative molecular field analysis

Summary The applicability of the comparative molecular field analysis (CoMFA) approach to describe the nonlinear dependence of biological activity on lipophilicity in 3D quantitative structure-activity relationships (QSAR) has been demonstrated. The results indicate that the CoMFA approach is appropriate for describing nonlinear effects in 3D QSAR studies.     

Comparative molecular field analysis and comparative molecular similarity index analysis studies on 1H NMR chemical shift of NH group of diaryl triazene derivatives

Comparative molecular field analysis (CoMFA), comparative molecular field analysis region focusing (CoMFA‐RF) for optimizing the region for the final partial least square analysis, and comparative molecular similarity indices analysis (CoMSIA) methods were employed to develop three‐dimensional quantitative structure–activity relationship (3D‐QSAR) models of ¹H NMR chemical shift of NH proton of diaryl triazene derivatives. The best orientation was searched by all‐orientation search (AOS) strategy to minimize the effect of the initial orientation of the structures. The predictive abilities of CoMFA‐RF and CoMSIA models were determined using a test set of ten compounds affording predictive correlation coefficients of 0.721 and 0.754, respectively, indicating good predictive power. For further model validation, cross validation (leave one out), progressive scrambling, and bootstrapping were also applied. The accuracy and speed of obtained 3D‐QSAR models for the prediction of ¹H NMR chemical shifts of NH group of diaryl triazene derivatives were greater compared to some computational well‐known procedures. Copyright © 2013 John Wiley & Sons, Ltd.     

Comparative molecular field analysis (CoMFA) of new herbicidal sulfonylurea compounds

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Calculation of hydrophobic parameters directly from three-dimensional structures using comparative molecular field analysis

Summary Capacity ratio (log k') values, which are a measure of hydrophobicity, were calculated directly from the three-dimensional structures of 17 furans and 54 triazines using the comparative molecular field analysis approach. The H₂O probe and the GRID force field, including hydrogen-bond potentials, yielded excellent correlations with the log k' values. Moreover, the predicted values of log k' from 14 additional triazine analogs showed excellent agreement with log k' values reported in the literature. Similar results were obtained for the octanol-water partition coefficients (log P) of 17 furans.     

A structure-activity relationship study of catechol-O-methyltransferase inhibitors combining molecular docking and 3D QSAR methods

A panel of 92 catechol-O-methyltransferase (COMT) inhibitors was used to examine the molecular interactions affecting their biological activity. COMT inhibitors are used as therapeutic agents in the treatment of Parkinson's disease, but there are limitations in the currently marketed compounds due to adverse side effects. This study combined molecular docking methods with three-dimensional structure-activity relationships (3D QSAR) to analyse possible interactions between COMT and its inhibitors, and to incite the design of new inhibitors. Comparative molecular field analysis (CoMFA) and GRID/GOLPE models were made by using bioactive conformations from docking experiments, which yielded q2 values of 0.594 and 0.636, respectively. The docking results, the COMT X-ray structure, and the 3D QSAR models are in agreement with each other. The models suggest that an interaction between the inhibitor's catechol oxygens and the Mg2+ ion in the COMT active site is important. Both hydrogen bonding with Lys144, Asn170 and Glu199, and hydrophobic contacts with Trp38, Pro174 and Leu198 influence inhibitor binding. Docking suggests that a large R1 substituent of the catechol ring can form hydrophobic contacts with side chains of Val173, Leu198, Met201 and Val203 on the COMT surface. Our models propose that increasing steric volume of e.g. the diethylamine tail of entacapone is favourable for COMT inhibitory activity.     

Automated docking of 82 N-benzylpiperidine derivatives to mouse acetylcholinesterase and comparative molecular field analysis with 'natural' alignment

Automated docking and three-dimensional Quantitative Structure-Activity Relationship studies (3D QSAR) were performed for a series of 82 reversible, competitive and selective acetylcholinesterase (AChE) inhibitors. The suggested automated docking technique, making use of constraints taken from experimental crystallographic data, allowed to dock all the 82 substituted N-benzylpiperidines to the crystal structure of mouse AChE, because of short computational times. A 3D QSAR model was then established using the CoMFA method. In contrast to conventional CoMFA studies, the compounds were not fitted to a reference molecule but taken in their 'natural' alignment obtained by the docking study. The established and validated CoMFA model was then applied to another series of 29 N-benzylpiperidine derivatives whose AChE inhibitory activity data were measured under different experimental conditions. A good correlation between predicted and experimental activity data shows that the model can be extended to AChE inhibitory activity data measured on another acetylcholinesterase and/or at different incubation times and pH level.     

Comparative molecular field analysis of non-steroidal aromatase inhibitors related to fadrozole

Summary A series of non-steroidal inhibitors of aromatase, structurally related to fadrozole (2), was investigated with the aim of developing a 3D QSAR model using the Comparative Molecular Field Analysis (CoMFA) technique. The alignment of the molecules was performed following two approaches (atom-by-atom and field fit), both starting from an initial hypothesis of superimposition of fadrozole to a steroidal inhibitor (3). From a number of CoMFA models built with different characteristics, one was recognized as the most statistically relevant; this one is discussed in detail. The features of the 3D QSAR model are consistent with those of other 3D and QSAR models of aromatase and its inhibitors.     

Molecular modeling of cytochrome P450 3A4

The three-dimensional structure of human cytochrome P450 3A4 was modeled based on crystallographic coordinates of four bacterial P450s: P450 BM-3, P450cam, P450terp, and P450eryF. The P450 3A4 sequence was aligned to those of the known proteins using a structure-based alignment of P450 BM-3, P450cam, P450terp, and P450eryF. The coordinates of the model were then calculated using a consensus strategy, and the final structure was optimized in the presence of water. The P450 3A4 model resembles P450 BM-3 the most, but the B helix is similar to that of P450eryF, which leads to an enlarged active site when compared with P450 BM-3, P450cam, and P450terp. The 3A4 residues equivalent to known substrate contact residues of the bacterial proteins and key residues of rat P450 2B1 are located in the active site or the substrate access channel. Docking of progesterone into the P450 3A4 model demonstrated that the substrate bound in a 6-orientation can interact with a number of active site residues, such as 114, 119, 301, 304, 305, 309, 370, 373, and 479, through hydrophobic interactions. The active site of the enzyme can also accommodate erythromycin, which, in addition to the residues listed for progesterone, also contacts residues 101, 104, 105, 214, 215, 217, 218, 374, and 478. The majority of 3A4 residues which interact with progesterone and/or erythromycin possess their equivalents in key residues of P450 2B enzymes, except for residues 297, 480 and 482, which do not contact either substrate in P450 3A4. The results from docking of progesterone and erythromycin into the enzyme model make it possible to pinpoint residues which may be important for 3A4 function and to target them for site-directed mutagenesis.     

Comparative molecular field analysis of artemisinin derivatives: Ab initio versus semiempirical optimized structures

Based on the belief that structural optimization methods, producing structures more closely to the experimental ones, should give better, i.e. more relevant, steric fields and hence more predictive CoMFA models, comparative molecular field analyses of artemisinin derivatives were performed based on semiempirical AM1 and HF/3-21G optimized geometries. Using these optimized geometries, the CoMFA results derived from the HF/3-21G method are found to be usually but not drastically better than those from AM1. Additional calculations were performed to investigate the electrostatic field difference using the Gasteiger and Marsili charges, the electrostatic potential fit charges at the AM1 level, and the natural population analysis charges at the HF/3-21G level of theory. For the HF/3-21G optimized structures no difference in predictability was observed, whereas for AM1 optimized structures such differences were found. Interestingly, if ionic compounds are omitted, differences between the various HF/3-21G optimized structure models using these electrostatic fields were found.     

Comparative molecular field analysis and molecular modeling studies of 20-(S)- camptothecin analogs as inhibitors of DNA topoisomerase I and anticancer/antitumor agents

Conformational studies and comparative molecular field analysis (CoMFA) were undertakenfor a series of camptothecin (CPT) analogs to correlate topoisomerase I inhibition with thesteric and electrostatic properties of 32 known compounds. The resulting CoMFA modelshave been used to make predictions on novel CPT derivatives. Using the newly derived MM3parameters, a molecular database of the 32 CPT analogs was created. Various point atomiccharges were generated and assigned to the MM3 minimized structures, which were used inpartial least-squares analyses. Overall, CoMFA models with the greatest predictive validitywere obtained when both the R- and S-isomers were included in the data set, andsemiempirical charges were calculated for MM3 minimized low-energy lactone structures. Across-validated R2 of 0.758 and a non-cross-validated R2 of 0.916 were obtained for MM3minimized structures with PM3 ESP charges for the 32 CPT analogs. The derived QSARequations were used to assign topoisomerase I inhibition values for compounds in this studyand compounds not included in the original data set. Prior to its appearance in the literature,an IC50 of 103 nM was predicted for the 10,11-oxazole derivative. This CoMFA predictedvalue compared favorably with the recently reported value of 150 nM. The CoMFA modelwas also evaluated by predicting the activities of recently reported 11-aza CPT and trionederivatives. The predicted activity (IC50 = 249 nM) for 11-aza CPT compared well with thereported value of 383 nM.     

Molar mass of main-chain bile acid-based oligo-esters measured by SEC, MALDI-TOF spectrometry and NMR spectroscopy: a comparative study

Bile acid-based polymers are promising new materials for biomedical applications. The determination of their molar mass, as for other novel polymers, has been difficult, due to the lack of suitable standards for size exclusion chromatography (SEC). In order to solve this problem, a family of main-chain bile acid-based oligo-esters has been synthesized by acyclic diene metathesis to be used as analogues in such analysis. These oligomers have been characterized by SEC, MALDI-TOF mass spectrometry and NMR spectroscopy. The results show that SEC with polystyrene standards tends to overestimate the molar mass of these materials and that a correction factor between 0.50 and 0.60 should be used for more accuracy.     

Molecular modeling studies of human immunodeficiency virus type 1 protease inhibitors using three‐dimensional quantitative structure‐activity relationship,virtual screening,and docking simulations

In this paper, two 3‐dimensional quantitative structure‐activity relationship models for 60 human immunodeficiency virus (HIV)‐1 protease inhibitors were established using random sampling analysis on molecular surface and translocation comparative molecular field vector analysis (Topomer CoMFA). The non–cross‐validation (r²), cross‐validation (q²), correlation coefficient of external validation (Q²_ext), and F of 2 models were 0.94, 0.80, 0.79, and 198.84 and 0.94, 0.72, 0.75, and 208.53, respectively. The results indicated that 2 models were reasonable and had good prediction ability. Topomer Search was used to search R groups in the ZINC database, 20 new compounds were designed, and the Topomer CoMFA model was used to predicate the biological activity. The results showed that 18 new compounds were more active than the template molecule. So the Topomer Search is effective in screening and can guide the design of new HIV/AIDS drugs. The mechanism of action was studied by molecular docking, and it showed that the protease inhibitors and Ile50, Asp25, and Arg8 sites of HIV‐1 protease have interactions. These results have provided an insight for the design of new potent inhibitors of HIV‐1 protease.     

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of thiazolone derivatives as hepatitis C virus NS5B polymerase allosteric inhibitors

Three-dimensional quantitative structure-activity relationship (3D-QSAR) models for a series of thiazolone derivatives as novel inhibitors bound to the allosteric site of hepatitis C virus (HCV) NS5B polymerase were developed based on CoMFA and CoMSIA analyses. Two different conformations of the template molecule and the combinations of different CoMSIA field/fields were considered to build predictive CoMFA and CoMSIA models. The CoMFA and CoMSIA models with best predictive ability were obtained by the use of the template conformation from X-ray crystal structures. The best CoMFA and CoMSIA models gave q (2) values of 0.621 and 0.685, and r (2) values of 0.950 and 0.940, respectively for the 51 compounds in the training set. The predictive ability of the two models was also validated by using a test set of 16 compounds which gave r (pred) (2) values of 0.685 and 0.822, respectively. The information obtained from the CoMFA and CoMSIA 3D contour maps enables the interpretation of their structure-activity relationship and was also used to the design of several new inhibitors with improved activity.     

Use of the hydrogen bond potential function in a comparative molecular field analysis (CoMFA) on a set of benzodiazepines

Summary The results of the GRID-Comparative Molecular Field Analysis (CoMFA) were compared with those of the SYBYL-CoMFA in a study of benzodiazepines. The results demonstrate that the hydrogen bonding function using the GRID H₂O probe in a CoMFA can successfully describe the hydrophobic effects of substituents without any bias or preconcept of their effects in the development.     

A comparative molecular field analysis (CoMFA) study using semiempirical, density functional, ab initio methods and pharmacophore derivation using DISCOtech on sigma 1 ligands

The Comparative Molecular Field Analysis (CoMFA) was developed to investigate a three-dimensional quantitative structure activity relationship (3D-QSAR) model of ligands for the sigma 1 receptor. The starting geometry of sigma-1 receptor ligands was obtained from the Tripos force field minimizations and conformations were decided from DISCOtech using the SYBYL 6.8. program. The structures of 48 molecules were fully optimized at the ab initio HF/3-21G* and semiempirical AM1 calculations using GAUSSIAN 98. The electrostatic charges were calculated using several methods such as semiempirical AM1, density functional B3LYP/3-21G*, and ab initio HF/3-21G*, MP2/3-21G* calculations within GAUSSIAN 98. Using the optimized geometries, the CoMFA results derived from the HF/3-21G method were better than those from AM1. The best CoMFA was obtained from HF/3-21G* optimized geometry and charges (R2 = 0.977). Using the optimized geometries, the CoMFA results derived from the HF/3-21G methods were better than those from AM1 calculations. The training set of 43 molecules gave higher R2 (0.989-0.977) from HF/3-21G* optimized geometries than R2 (0.966-0.911) values from AM1 optimized geometries. The test set of five molecules also suggested that HF/3-21G* optimized geometries produced good CoMFA models to predict bioactivity of sigma 1 receptor ligands but AM1 optimized geometries failed to predict reasonable bioactivity of sigma 1 receptor ligands using different calculations for atomic charges.     

Prediction of the three-dimensional structure of the human Fas receptor by comparative molecular modeling

The Fas antigen, a cell surface receptor belonging to the tumor necrosis factor receptor(TNFR) superfamily, triggers programmed cell death (apoptosis) in the immune system. Thethree-dimensional structure of Fas and molecular details of the interaction between Fas andits ligand are currently unknown. A three-dimensional model of the Fas extracellular regionwas generated by comparative modeling. Inverse folding analysis suggested goodsequence–structure compatibility of the model and thus reasonable accuracy. Themodel was analyzed in the light of information provided by studies on TNFR and CD40,another member of the TNFR family, and the Fas ligand binding site was predicted.     

Molecular structural investigations of quinoxaline derivatives through 3D-QSAR,molecular docking,ADME prediction and pharmacophore modeling studies for the search of novel antimalarial agent

In the present article, a dataset of 63 quinoxaline derivatives were taken for antimalarial activity and pharmacophore were developed. Atom based method was used to develop a three dimensional quantitative structure activity relationship (3D-QSAR) model. On comparison of all statistical parameters, model AHRRR23 was found to be the most effective and predictive QSAR model as it satisfied all statistical parameters of a good model. The model AHRRR23 showed an adequate R² value for the training set 0.9446, good predictive power with Q² of 0.6409, good F- value, low SD 0.1218 value and outstanding Pearson-R values and low RMSE 0.2779 values of the model. The docking studies also gives very good results with good RMSD values. 3D QSAR, docking and ADME studies exhibits that the developed model could be employed as a potential lead for further study as antimalarial drug.     

Fatty acid composition of wild edible mushrooms species: A comparative study

A comparative study was developed on the total fatty acids composition of twelve wild edible mushroom species (Suillus bellini, Suillus luteus, Suillus granulatus, Hygrophorus agathosmus, Amanita rubescens, Russula cyanoxantha, Boletus edulis, Tricholoma equestre, Fistulina hepatica, Cantharellus cibarius, Amanita caesarea and Hydnum rufescens). In order to define qualitative and quantitative profiles, combined fatty acids were hydrolyzed with potassium hydroxide/methanol and all free compounds were derived to their methyl ester forms with methanolic boron trifluoride, followed by analysis by GC-MS. Thirty fatty acids were determined. As far as we know, the fatty acid profiles of A. caesarea and H. rufescens are described for the first time. As for the remaining species, a high number of new compounds were identified, which much improved the knowledge about their fatty acids profiles. In general, oleic, linoleic, palmitic and stearic acids were present in highest contents. Polyunsaturated and monounsaturated fatty acids, valuable healthy compounds for humans, predominated over saturated fatty acids for all the studied mushroom species. R. cyanoxantha presented the highest fatty acids amounts, while B. edulis was the poorest species. By Agglomerative Hierarchic Cluster Analysis the studied species were gathered in 5 groups, based in their fatty acid patterns.