Insight into the structural requirement of aryltriazolinone derivatives as angiotensin II AT1 receptor: 2D and 3D-QSAR k-Nearest Neighbor Molecular Field Analysis approach

Abstract

Quantitative structure–activity relationship (QSAR) studies were carried out on a series of 48 recently synthesised N2-aryltriazolinone biphenyl sulphonamides derivatives to investigate the structural requirements of their inhibitory activities against angiotensin II AT1 receptor. Partial least square (PLS) methodology coupled with various feature selection methods, viz. stepwise (SW), genetic algorithm, and simulated annealing, was 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 correlation coefficient r2 = 0.8456 and cross-validated squared correlation coefficient q2 = 0.7359 with external predictive ability of pred_r2 = 0.8142 and pred_r2se = 0.2817 was developed by SW–PLS with the descriptors like T_O_O_2, slogp, T_N_F_4, H-acceptor count, and Chi3cluster. Molecular field analysis was used to construct the best 3D-QSAR model using SW–PLS method, showing good correlative and predictive capabilities in terms of q2 = 0.8201 and pred_r2 = 0.7894. The steric, electrostatic, and hydrophobic descriptors at the grid points S_837, S_1010, E_940, E_285, E_1143, and H_903 play an important role in the design of new molecule. The results of this study may be useful on the designing of more potent analogs as antihypertensive agents.