Discovery of potent antihypertensive ligands substituted imidazolyl biphenyl sulfonylureas analogs as angiotensin II AT1 receptor antagonists by molecular modelling studies.

To elucidate the structural properties required for antihypertensive activity, three different molecular modeling techniques; two-dimensional Quantitative structure activity relationship (2D-QSAR), Group-Based Quantitative structure activity relationship (G-QSAR), and three-dimensional Quantitative structure activity relationship (3D-QSAR) studies have been carried out on a series of substituted imidazolyl biphenyl sulfonylureas derivatives. Multiple linear regressions methodology, viz. variable simulated annealing (SA) and stepwise (SW) methods, was applied to derive models which were further validated for statistical significance and predictive ability by internal and external validation. The best 2D-QSAR model was selected, having showed best predictability of activity with cross validated value (q2) = 0.7866, coefficient of determination (r2) =0.8003. The r2_pred value of 0.7651 indicates predictability of test set analogues and reveals a significant and robust model and best G-QSAR model having r2 = 0.7459 and q2 = 0.6712 with pred_r2 = 0.7105 was developed by SA -MLR. Using k-nearest neighbour (kNN) approach, various 3D QSAR models were generated and selected on the basis of q2 and predictive r2 values. The analyzed best 3D-QSAR model revealed a good fit, having r2 value of 0.8240 and q2 value of 0.7523. The predictive power of the model generated was validated using a test set comprising molecules with pred_r2 value of 0.7299. The results of two-dimensional QSAR, Group based QSAR showed that a combination of revealed the key role of Baumann's alignment independent topological descriptors along with other descriptors such as the number of hydrogen bond acceptors, hydrogen bond donors, rotatable bonds indices properties and auto-correlation descriptors of different atomic properties could be explored to design potent antihypertensive agents. Finally, it is hoped that the work presented here will play an important role in understanding the relationship of physiochemical parameters with structure and biological activity.