Comparative Molecular Field Analysis Studies Research Articles

Combined 3D-QSAR, Molecular Docking, and Molecular Dynamics Study on Piperazinyl-Glutamate-Pyridines/Pyrimidines as Potent P2Y12 Antagonists for Inhibition of Platelet Aggregation

An unusually large data set of 397 piperazinyl-glutamate-pyridines/pyrimidines as potent orally bioavailable P2Y(12) antagonists for inhibition of platelet aggregation was studied for the first time based on the combination of three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, and molecular dynamics (MD) methods. The comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) studies have been performed with a training set of 317 compounds, estimating three superimposition methods. The best CoMFA and CoMSIA models, derived from superimposition I, shows leave-one-out cross-validation correlation coefficients (Q(2)) of 0.571 and 0.592 as well as the conventional correlation coefficients (R(2)(ncv)) of 0.814 and 0.834, respectively. In addition, the satisfactory results, based on the bootstrapping analysis and 10-fold cross-validation, further indicate the highly statistical significance of the optimal models. The external predictive abilities of these models were evaluated using a prediction set of 80 compounds, producing the predicted correlation coefficients (R(2)(pred)) of 0.664 and 0.668, respectively. The key amino acid residues were identified by molecular docking, and the stability and rationality of the derived molecular conformations were also validated by MD simulation. The good concordance between the docking results and CoMFA/CoMSIA contour maps provides helpful clues about the rational modification of molecules in order to design more potent P2Y(12) antagonists. We hope the developed models could provide some instructions for further synthesis of highly potent P2Y(12) antagonists.

Pharmacophore Screening on Piperidinecarboxamides Derivatives Based on GALAHAD and CoMFA Models

In order to discover the novel anticonvulsant drugs, pharmacophore screening of the anticonvulsant inhibitors was enforced. Genetic Algorithm with Linear Assignment for Hypermolecular Alignment of Datasets (GALAHAD) and Comparative Molecular Field Analysis (CoMFA) studies were combined to implement our research. Firstly, multiple models were generated using GALAHAG based on high active molecules. Secondly, several of them were validated using the CoMFA study. Finally, a good values of q2 from training set and promising predictive power from test set were obtained based on one model simutaneously. One model had been selected as the most reasonable pharmacophore model. The results of the CoMFA study based on the model 1 suggested that both steric and electrostatic interactions played important roles.

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of some benzimidazole derivatives with trichomonicidal activity

Trichomonosis is a common sexually transmitted infectious disease linked to reproductive health complications. Recently, the benzimidazole nucleus has emerged as a promising scaffold to develop new trichomonicidal agents. Despite the fact that large amounts of experimental data have been accumulated over the past eight years, no quantitative studies have yet been reported on this class of compounds. In our effort to develop new antiparasitic benzimidazole derivatives, we report in this paper CoMFA and CoMSIA studies with an initial set of 70 benzimidazole derivatives with trichomonicidal activity. Four CoMFA models and eight CoMSIA models were generated; ten of these models had values of r 2 > 0.6 and q 2 > 0.5. The best CoMFA model had r 2 = 0.936 and q 2 = 0.634, and the best CoMSIA model had r 2 = 0.858 and q 2 = 0.642. These models were generated by using two conformer selection methodologies (minimum energy conformations and 3D similarity), and three charge types (Mulliken, Gasteiger-Hükel and electrostatic potential atomic charges). The putative active tautomers of 1 H-benzimidazole derivatives were selected using 3D-QSAR calculations. All models were validated via an external test set with 13 molecules. The best models satisfied additional validation criteria. The contour maps generated show the most important features that a benzimidazole derivative should have for trichomonicidal activity; they also, suggest that substituents at the 2- and 6-positions are important in the generation of derivatives with strong activity.

Predicting anti-cancer activity of quinoline derivatives: CoMFA and CoMSIA approach

The 3D quantitative structure-activity relationships of 31 quinoline nuclei containing compounds and their biological activity have been investigated to establish various models. The comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) studies resulted in reliable and significant computational models. The obtained CoMFA model showed high predictive ability with q2 = 0.592, r2 = 0.966 and standard error of estimation (SEE) = 0.167, explaining majority of the variance in the data with two principal components. Predictions obtained with CoMSIA steric, electrostatic, hydrophobic, hydrogen-bond acceptor and donor fields (q2 = 0.533, r2 = 0.985) showed high prediction ability with minimum SEE (0.111) and four principal components. The information obtained from the CoMFA and CoMSIA contour maps can be utilized for the design and development of topoisomerase-II inhibitors for synthesis.

Ligand‐Based 3D‐QSAR Studies of Diaryl Acyl‐sulfonamide Analogues as Human Umbilical Vein Endothelial Cells Inhibitors Stimulated by VEGF

Diaryl acylsulfonamide derivatives were reported as Human Umbilical Vein Endothelial cell (HUVEC) inhibitors, stimulated by Vascular Endothelial Growth Factor (VEGF). VEGF has angiogenic property to cause colorectal cancer. A ligand-based 3D-QSAR technique was carried out on diaryl acylsulfonamide derivatives by using Comparative Molecular Field Analysis (CoMFA) studies to find relations between biological activities of inhibitors and their structures. In absence of binding mechanism for the ligand with VEGF receptor, current study hopes to shed some light on the inhibition mechanism of the ligands with HUVEC. 3D-QSAR technique was applied to a set of fifty ligands in order to facilitate the design of more potent inhibitors. However, the maximum cross-validated correlation coefficient value was found to be 0.417. The value is relatively low when compared to the usual acceptable cross-validated correlation coefficient, but no further improvements were observed by applying different available options. Therefore, the final model was used for further analysis. Additionally, the resulted CoMFA model was validated by an external set of 10 compounds yielding surprisingly, a satisfactory correlation coefficient value (r(2) (pred) ) 0.80. Moreover, the analysis of the individual generated 3D contours helped in understanding the possible structural modifications of molecules to improve the inhibitory potency.

3D-QSAR studies on purine-carbonitriles as cruzain inhibitors: comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA)

Cruzain has been identified as the major cysteine protease of Trypanosoma cruzi, the etiological cause of Chaga's disease. For this reason, many efforts have been undertaken to design new inhibitors against this enzyme. Recently, molecules having a purine or triazine nucleus have been reported as potent non-peptidic inhibitors of cruzain. In order to gain an insight into the structural requirements that can lead to the improvement of the activity of these molecules, in this paper we report the CoMFA and CoMSIA studies of a series of purine-carbonitriles as cruzain inhibitors. Quantum semi-empirical calculations of the inhibitors inside the active site of cruzain were used as an approach to obtain reliable conformations for molecular alignment. Two different molecular alignments were used, resulting in 3 CoMFA models and 31 CoMSIA models. These models correspond to all of the possible combinations among five fields: steric, electrostatic, hydrophobic, hydrogen bond donor, and hydrogen bond acceptor. Highly predictive models were obtained. Based on the q2 values, the best CoMFA model had an r2 = 0.98 and a q2 = 0.73, whereas the best CoMSIA model retrieved an r2 = 0.88 and a q2 = 0.62. All models were validated with a rigorous procedure using an external test set. Contour maps obtained from these models show a preference toward the purine ring and indicate that bulky groups with a negative potential at the 3- and 5-positions of the phenyl ring are important structural requirements for inhibitory activity against cruzain.

Comparative molecular field analysis and comparative molecular similarity indices analysis studies of α-ketothiazole arginine analogues inhibitors of coagulation factor XIa

Factor XIa is a serine protease expressed as a zymogen that is converted to its active form, XIa, by factor XIIa and by thrombin, and plays a major role in amplification of thrombotic response to maintaining clot activity. The 3D-QSAR study of α-ketotiazole arginine analogue inhibitors of coagulation factor XIa were developed using CoMFA and CoMSIA models that showed excellent internal predictability and consistency, while validation using test-set compounds yielded a good predictive power for pIC50. The CoMFA model with steric and electrostatic fields provided satisfactory statistical data (q2 = 0.632 and q2cv = 0.957) and CoMSIA model with steric, electrostatic, hydrophobic, H-bond donor and acceptor exhibited q2 = 0.683 and q2cv = 0.853. Interaction between receptor and ligands most importantly are H-bond hydrogens, salt bridge. The information obtained from both CoMFA and CoMSIA 3D contour maps may be used in the design of new coagulation factor XIa inhibitors.

Key Features for Designing Phosphodiesterase-5 Inhibitors

Phosphodiesterase superfamily is the key regulator of 3′,5′-cyclic guanosine monophosphate (cGMP) decomposition in human body. Phosphodiesterase-5 (PDE-5) inhibitors, sildenafil, vardenafil and tadalafil, are well known oral treatment for males with erectile dysfunction. To investigate the inhibitory effects of traditional Chinese medicine (TCM) compounds to PDE-5, we performed both ligand-based and structure-based studies on this topic. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) studies were conducted to construct three dimensional quantitative structure-activity relationship (3D-QSAR) models of series of known PDE-5 inhibitors. The predictive models had cross-validated, q2, and non cross-validated coefficient, r2, values of 0.791 and 0.948 for CoMFA and 0.724 and 0.908 for CoMSIA. These two 3D-QSAR models were used to predict activity of TCM compounds. Docking simulations were performed to further analyze the binding mode of training set and TCM compounds. A putative binding model was proposed based on CoMFA and CoMSIA contour maps and docking simulations; formation of pi-stacking, water bridge and specific hydrogen bonding were deemed important interactions between ligands and PDE-5. Of our TCM compounds, engeletin, satisfied our binding model, and hence, emerged as PDE-5 inhibitor candidate. Using this study as an example, we demonstrated that docking should be conducted for qualitative purposes, such as identifying protein characteristics, rather than for quantitative analyses that rank compound efficacy based on results of scoring functions. Prediction of compound activity should be reserved for QSAR analyses, and scoring functions and docking scores should be used for preliminary screening of TCM database (http://tcm.cmu.edu.tw/index.php).

CoMFA and CoMSIA studies on 5-hydroxyindole-3-carboxylate derivatives as 5-lipoxygenase inhibitors: Generation of homology model and docking studies

In this study, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of 2-substituted 5-hydroxyindole-3-carboxylate derivatives as potent 5-LOX inhibitors with IC50 values ranging from 0.031 to 13.4μM. Two datasets of same molecules were prepared with two different partial atomic charges; one with Gasteiger–Huckel and another with the ESPFIT charges obtained from the gaussian package. CoMFA and CoMSIA models were generated for both the datasets and the results were analysed. With regard to the non-cross validated r2 values (rncv2) and cross-validated q2 values (qcv2) of the resulting QSAR models, the dataset with ESPFIT charges yielded higher values; hence it was further used in the study. The CoMFA and CoMSIA models have been further validated for their stability and robustness using group validation and bootstrapping techniques and for their predictive abilities using an external test set of ten compounds. The predictive power of the CoMSIA model was higher than the CoMFA model, the high predictive r2 values of the test set reveals that the models prove to be useful tools for activity prediction of newly designed 5-LOX inhibitors. The ESPFIT-derived charges yielded better models than those based on charges calculated from Gasteiger–Huckel charges. We generated a homology model for human 5-LOX and identified the key residues at the binding site. The 3D-QSAR models were compared with the interactions at the active site to further elucidate the accuracy of the models. The data generated from 3D-QSAR study was used to design potential 5-LOX inhibitors.

3D-QSAR CoMFA and CoMSIA studies on a set of diverse α1a-adrenergic receptor antagonists

The α-adrenergic receptors (α-ARs) modulate a number of intracellular processes and among these α1a-adrenergic receptors play an important role in the regulation of physiological processes related to cardiovascular system. In view of its therapeutic potential, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) studies were performed on a set of diverse α-AR antagonists to understand the structural factors affecting their antagonistic activity where both CoMFA (qtrain2 = 0.709, rtrain2 = 0.962, and rpredictive2 = 0.629) and CoMSIA (qtrain2 = 0.648, rtrain2 = 0.949, and rpredictive2 = 0.656) models gave statistical significant results. The generated CoMFA and CoMSIA models suggest that steric, electrostatic and hydrophobic interactions play an important role in describing the variation in antagonistic activity. Therefore, the models may be useful in the identification and optimization of novel scaffolds with potent α1a-adrenergic receptor antagonistic activity.

Self-Organizing Molecular Field Analysis on Pyridazine Analogues as Protein Tyrosine Phosphatase 1B (PTP 1B) Inhibitors

A 3D-QSAR study has been performed using Self-organizing molecular field analysis (SOMFA) on a novel class of pyridazine analogues as non-competitive and reversible inhibitors of PTP 1B. SOMFA is a novel 3D-QSAR methodology, similar to both comparative molecular field analysis (CoMFA) and molecular similarity studies. SOMFA studies have been performed to correlate chemical structures of pyridazine analogues with their observed PTP 1B inhibitory activity. The master grid obtained for the various SOMFA models indicates electrostatic and shape potential contributions. These can be mapped back onto the structural features relating to trends in activities of the molecules. On the basis of the spatial arrangement of the various shape and electrostatic potential contributions, new inhibitors of PTP 1B can be designed with improved spectrum of activity for the management of type 2 diabetes. Keywords: Insulin, NIDDM, PTP 1B, Pyridazine, 3D-QSAR, SOMFA

ChemInform Abstract: Development of Pharmacophore Alignment Models as Input for Comparative Molecular Field Analysis of a Diverse Set of Azole Antifungal Agents.

Molecular modeling studies were performed on a diverse set of 24 cytochrome P-45014αDM inhibiting azole antifungals that demonstrate different degrees of biological activity. The studied compounds, which have been reported to be active in vitro against Candida albicans, were divided into a training set of 20 compounds and a test set of 4 compounds. In an effort to develop a ligand-binding model for the cytochrome P-45014αDM receptor, a pharmacophore mapping program (Apex-3D) was used to search structural features that are common to ligands that exhibit moderate to high antifungal activity. Apex-3D then was utilized to propose a common biophoric region that included one low-energy conformation of each compound in the training set. These aligned structures suggested a three-point pharmacophore map (two atom-centered descriptors and one aromatic ring centroid) for the azole antifungals. The resulting alignment was used in a comparative molecular field analysis (CoMFA) study in an attempt to correlate the ste...

Isolation, biological evaluation and 3D-QSAR studies of insecticidal/narcotic sesquiterpene polyol esters

For the first time, a set of (43) natural sesquiterpene polyol esters isolated from the root bark of Celastrus angulatus Maxim and Euonymus japonicus Thunb were subjected to 3D-QSAR comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) studies, with the aim of proposing novel sesquiterpene-based compounds with optimal narcotic or insecticidal activities. The established 3D-QSAR models exhibit reasonable statistical quality and prediction capabilities, with internal cross-validated Q (2) values of ∼ 0.5 and external predicted R (2) values of >0.9, respectively. The relative contributions of the steric/electrostatic fields of the 3D-QSAR models show that the electronic effect governs the narcotic activities of the molecules, but the hybrid effect of the electrostatic and hydrophobic interactions is more influential in the insecticidal activities of the compounds. These findings may have valuable implications for the development of novel natural insecticides.

CoMFA and CoMSIA 3D-QSAR studies on quionolone caroxylic acid derivatives inhibitors of HIV-1 integrase

A series of quionolone caroxylic acid derivatives inhibitors of HIV-1 integrase were subjected to three-dimensional quantitative structure–activity relationship (3D-QSAR) studies using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches. The CoMFA model includes steric and electrostatic fields for the training set with the cross-validated q 2 value of 0.67 and the non-cross-validated r 2 value of 0.98. The cross-validated q 2 value of CoMSIA Model is 0.76 and the non-cross-vaildated r 2 value is 0.99. From the cross-validated results, it can be seen that the CoMSIA model has a better predictive ability than CoMFA model. Based on the above results, the CoMFA and CoMSIA analyses can be used in the design of more potent HIV-1 integrase inhibitors.

CoMFA and CoMSIA studies on HIV-1 attachment inhibitors

A series of human immunodeficiency virus type 1 (HIV-1) attachment inhibitors were subjected to ligand-based three-dimensional quantitative structure–activity relationship (3D-QSAR) studies using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches. The CoMFA model yielded satisfactory statistical data with the cross-validated q 2 value of 0.589 and the non-cross-validated r 2 value of 0.963. The cross-validated q 2 value of CoMSIA Model was 0.621 and the non-cross-validated r 2 value was 0.972. From the cross-validated results, it can be seen that the CoMSIA model has a better predictive ability than CoMFA model. Based on the above results, the CoMFA and CoMSIA analyses can be used in the design of more potent HIV-1 attachment inhibitors.

CoMFA and CoMSIA Studies on Inhibitors of HIV‐1 Integrase ‐ Bicyclic Pyrimidinones

To understand the structural requirements of HIV‐1 integrase inhibitors and to design new ligands against human HIV‐1 integrase with enhanced inhibitory potency, a 3D QSAR (quantitative structure‐activity relationship) study with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) for a dataset of 35 bicyclic pyrimidinones which are inhibitors of human HIV‐1 integrase was performed. QSAR models were computed with Sybyl. The 3D QSAR model showed very good statistical result, namely q2, r2 and r2pred values were high for both CoMFA and CoMSIA. Based on the high values for q2 and r2 we are confident that the 3D QSAR model gives good predictions that may be used to design better HIV‐1 integrase inhibitors. The CoMFA and CoMSIA models reveal that steric and electrostatic fields contribute significantly with biological activities of the studied compounds.

Theoretical studies on pyrimidine substituent derivatives as dual inhibitors of AP-1 and NF-κB

Theoretical studies on the three-dimensional (3D) quantitative structure-activity relationship (QSAR) and mechanisms of action of a series of pyrimidine substituent derivatives as dual inhibitors of AP-1 and NF-kappaB were carried out using comparative molecular field analysis (CoMFA) and docking methods. The established 3D-QSAR model exhibits a satisfying statistical quality and prediction ability. Docking results show somewhat lower average values of the flexible and rigid energy scores in the chosen binding sites. The docking analysis offers appropriate orientations and conformations of these compounds at the binding sites to both AP-1 and NF-kappaB in good agreement with the 3D-QSAR model from CoMFA. The combined CoMFA and docking study suggests the following substituent selections: substituent R(2) should be a kind of H-N-thienyl or CH(3)-N-thienyl group; substituent R(5) should be a kind of COO-tBu or COOEt group; and substituent R(4) should be a CH(2)CH(3) or 2-thienyl group. The docking analysis also shows that the binding sites fall just at the joint regions between AP-1 (or NF-kappaB) and DNA, where these compounds can effectively prevent free AP-1 and NF-kappaB from binding to DNA, and this may be the reason that derivatives with pyrimidine substituents have an inhibition function. In addition, a very interesting finding was that the binding sites of both AP-1 and NF-kappaB have a common structural characteristic, thereby providing a reasonable explanation for the dual inhibition functions of these compounds towards both AP-1 and NF-kappaB. These theoretical results help to deepen our understanding of the inhibition mechanism of these pyrimidine substituent derivatives, and will aid in directing further drug-molecular design.

CoMFA and molecular docking studies of benzoxazoles and benzothiazoles as CYP450 1A1 inhibitors

For better understanding of the molecular interactions of inhibitors with CYP450 1A1, a series of benzoxazoles and benzothiazoles were analyzed by comparative molecular field analysis (CoMFA) and molecular docking. Two conformer-based alignment strategies were employed to construct reliable CoMFA models. The best CoMFA model yielded a predictive correlation coefficient r 2 pred value of 0.809. Furthermore, a three-dimensional model of CYP450 1A1 was generated by homology modeling using CYP450 1A2 as a template, and docking of 48 CYP450 1A1 inhibitors into the putative binding sites of the CYP450 1A1 were studied. The results obtained from this study will be helpful in the design of potentially active CYP450 1A1 inhibitors.

Docking and 3D-QSAR Studies on Isatin Sulfonamide Analogues as Caspase-3 Inhibitors

To provide insight of their inhibition mechanism and facilitate the design of more potent ligands, a series of 59 isatin sulfonamide analogues were docked to the X-ray structure of caspase-3, one of the important cysteine aspartyl-specific execution proteases in apoptosis, and their binding conformations were analyzed by 3D-QSAR studies. Comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) studies suggest that both steric and electrostatic interactions contribute to the compounds' binding affinity, with the major contribution arising from hydrophobic interactions. The models show excellent correlation and high predictive power even evaluated by the most stringent criteria for a QSAR model. The results of this work demonstrate that structure-based design methods (such as docking) cultivate the development of reliable QSAR models; they also illustrate the utility of this procedure in design of new potent caspase-3 ligands.

Synthesis, Herbicidal Activities and Comparative Molecular Field Analysis Study of Some Novel Triazolinone Derivatives

A series of novel triazolinones were synthesized and their structures were characterized by (1)H NMR, elemental analysis and single-crystal X-ray diffraction analysis. The herbicidal activities were evaluated against Echinochloa crusgalli (L.) Beauv., Digitaria adscendens, Brassica napus and Amaranthus retroflexus. The herbicidal activity data indicated that the title compounds had higher activities with substituted benzyl group moieties than with other groups such as sulfonyl, alkyl, etc. To further investigate the structure-activity relationship, comparative molecular field analysis was performed on the basis of herbicidal activity data. Both the steric and electronic field distributions of comparative molecular field analysis are in good agreement in this work. The results showed that a bulky and electronegative group around the ortho- or para-positions of the benzene ring would possibly lead to higher activity. Based on the comparative molecular field analysis, compound I-23 was designed and synthesized, which display as good herbicidal activities as the commercial herbicide, carfentrazone-ethyl. The activity against Digitaria adscendens is 66.1% under pre-emergence at 300 g of a.i./ha.