Comprehensive two and three-dimensional QSAR studies of 3-substituted 6-butyl-1,2dihydropyridin-2-ones derivatives as angiotensin II receptor antagonists

Abstract

In this paper, an attempt was made to develop a two and three-dimensional QSAR models on a series of 3-substituted 6-butyl-1,2 dihydropyridin-2-ones derivatives acting as angiotensin II receptor antagonists using partial least squares regression method. Various 2D descriptors were calculated and used in the present analysis. For model validation, the dataset was divided into various training and test sets using random selection procedures. The whole dataset was divided into training set (24 compounds) and test set (5 compounds). The statistically significant best 2D-QSAR model having correlation coefficient (r 2 = 0.9062) was selected for further study. The model was further validated by means of crossed squared correlation coefficient (q 2 = 0.7314 and pred_r 2 = 0.8133) which shows model has good predictive ability. The optimum QSAR model showed that the parameters SdsCHE-index, T_N_N_3, fluorines count, and SaaNHE-index contributed highly positive, while SsCH3count contributed negatively for antihypertensive activity. Using kNNMFA approach, various 3D-QSAR models were generated and selected on the basis of q 2 and predictive r 2 values. 3D-QSAR study was performed using k-nearest neighbor molecular field analysis approach for steric, electrostatic, and hydrophobic fields. Molecular field analysis was used to construct the best 3D-QSAR model using simulated annealing method. The significant best 3D-QSAR model-6 having model with good external and internal predictivity for the training and test sets has shown cross-validation (q 2) and external validation (pred_r2) values of 0.8534 and 0.8020, respectively. The steric, electrostatic, and hydrophobic descriptors at the grid points S_415, S_1059, E_1523, E_1045, E_1308, and H_153 play an important role in the design of new molecule. This model was found to yield reliable clues for further optimization of 3-substituted 6-butyl-1,2dihydropyridin-2-ones in the data set. The information rendered by 2D- and 3D-QSAR models may lead to a better understanding of structural requirements of 3-substituted 6-butyl-1,2dihydropyridin-2-ones derivatives and also aid in designing novel potent antihypertensive molecules.