Abstract
This study investigated 3D quantitative structure–activity relationships (QSAR) for a range of substituted benzimidazole derivatives as AngII-AT1 receptor antagonists by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA). The alignment strategy was used for these compounds by means of Distill function defined in SYBYL X 1.2. The best CoMFA and CoMSIA models were obtained for the training set compounds was statistically significant with leave-one-out (LOO) validation correlation coefficient (q2) of 0.613 and 0.622, cross validated coefficient (r2 cv) of 0.617 and 0.607, respectively and conventional coefficient (r2 ncv) of 0.886 and 0.859, respectively. Both the models were validated by a test set of 18 compounds giving satisfactory predicted correlation coefficient (r2 pred) of 0.714 and 0.549 for CoMFA and CoMSIA models, respectively. Generated 3D QSAR models were used for the prediction of pIC50 of an external dataset of 10 compounds for predictive validation, which gave conventional r2 of 0.893 for CoMFA model, and 0.774 for CoMSIA model. We identified some key features in substituted benzimidazole derivatives, such as the importance of lipophilicity and H-bonding at 2- and 5, 6, 7- position of benzimidazole ring, respectively, for good antagonistic activity. CoMFA and CoMSIA models generated in this work provide useful information for the design of new compounds and helped in prediction of antagonistic activity.
Keywords: 3D QSAR, AngII, ARBs, CoMFA, CoMSIA, Substituted benzimidazole derivatives.
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