Structural insights for substituted acyl sulfonamides and acyl sulfamides derivatives of imidazole as angiotensin II receptor antagonists using molecular modeling approach

Molecular modeling studies were carried out on a series of substituted acyl sulfonamides and acyl sulfamides derivatives of imidazole as angiotensin II AT(1) receptor antagonists in order to determine the structural properties required for their antihypertensive activity. To elucidate the structural properties required for antihypertensive activity, four different molecular modeling techniques; two-dimensional (2D-QSAR), Group-Based QSAR (G-QSAR), 3D-QSAR and pharmacophore identification studies have been carried out on a series of substituted acyl sulfonamides and acyl sulfamides derivatives of imidazole. The partial least square (PLS) regression method and kNN-MFA methodology coupled with feature selection methods viz., stepwise (SW) and simulated annealing (SA) were applied to derive QSAR models which were further validated for statistical significance and predictive ability by internal and external validation. The statistically significant best 2D-QSAR model having r(2) = 0.8711 and q(2) = 0.8054 with pred_r(2) = 0.8410 was developed by SW-PLS and best G-QSAR model having r(2) = 0.8196 and q(2) = 0.7299 with pred_r(2) = 0.7693 was developed by SW-PLS method. The best 3D-QSAR model using SA-kNN-MFA method, showing good correlative and predictive capabilities in terms of q(2) = 0.7862 and pred_r(2) = 0.7119. The contour maps generated by the kNN models were used to identify the key structural requirements responsible for the biological activity. Continuing with substituted acyl sulfonamides and acyl sulfamides derivatives of imidazole, chemical feature based pharmacophore model with lowest RMSD value (0.0436 A), consists of one AroC feature (aromatic), two AlaC features (aliphatic), one HAc (hydrogen bond acceptor), and one negative ionizable was developed. It could rationalize the antihypertensive activity profile of many compounds used in such study as well as the important structural features responsible for antihypertensive activity. The findings of these molecular modeling studies can serve as a useful guide for future rational design of potential agents with better antihypertensive activity. (C) 2013 Taiwan Institute of Chemical Engineers. Published by Elsevier B.V. All rights reserved.