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 modelling 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 and stepwise 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 [Formula: see text], coefficient of determination [Formula: see text]. The [Formula: see text]_pred value of 0.7651 indicates predictability of test set analogues and reveals a significant and robust model, and best G-QSAR model having [Formula: see text] and [Formula: see text] with pred_[Formula: see text] was developed by SA-MLR. Using k-nearest neighbour approach, various 3D-QSAR models were generated and selected on the basis of [Formula: see text] and predictive [Formula: see text] values. The analysed best 3D-QSAR model revealed a good fit, having [Formula: see text] value of 0.8240 and [Formula: see text] value of 0.7523. The predictive power of the model generated was validated using a test set comprising molecules with pred_[Formula: see text] value of 0.7299. The results of two-dimensional QSAR and 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 SsssCH count, SaasCE-index, SsOHcount indices 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.