Comparative pharmacophore modeling and QSAR studies for structural requirements of some substituted 2-aminopyridines derivatives as inhibitors nitric oxide synthases.

Abstract

The present studies are an attempt in this direction seeking for the development and comparison of QSAR models of substituted 2-aminopyridines derivatives as inhibitors of nitric oxide synthases by different feature selection methods. Comparing the two different feature selection methods, it is implicit that the model built with the selected variables by simulated annealing (SA) method gives better prediction in case of 2D and 3D QSAR modeling. The QSAR study was carried out on V-life Molecular Design Suite software and the derived best QSAR model was derived by partial component regression (PCR) method. The statistically significant best model with high correlation coefficient (r2 = 0.8408) was selected for further study. The model was further validated by means of crossed squared correlation coefficient (q2 = 0.7270 and pred r2 = 0.7889) which shows model has good predictive ability. 3D-QSAR analysis has been performed on a series of substituted 2-aminopyridines derivatives as which were screened as inhibitors of nitric oxide synthases, using the simulated annealing and step wise k-nearest neighbour Molecular Field Analysis. The best QSAR model showed q2 = 0.8377, r2 = 0.8739 and standard error = 0.1954. It was observed that steric properties predicted by k-nearest neighbour MFA contours can be related to inhibitors of nitric oxide synthases. The predictive ability of the resultant model was evaluated using a test set molecules and the predicted r2 = 0.8159. The distances between the pharmacophore sites were measured in order to confirm their significance to the activities. The results reveal that the acceptor (acc), donor (don), aliphatic and aromatic pharmacophore properties are favorable contours sites for both the activities. The two dimensional and k-nearest neighbour contour plots required for further understanding of the relationship between structural features of substituted 2-aminopyridines derivatives and their activities which should be applicable to design newer potential inducible nitric oxide synthases.