Molecular modelling studies for the discovery of new substituted pyridines derivatives with angiotensin II AT1 receptor antagonists.

A QSAR study has been performed on a series of pyridines derivatives with potent angiotensin II AT1 receptor antagonists. Structural features responsible for the activity of the compounds were characterized by using topological, electrotopological, group based and 3D descriptors, calculated from the Molecular Design Suite software (V-life MDS 3.5). To elucidate the structural properties required for antihypertensive activity, four different molecular modeling techniques; two-dimensional, Group-based (G-QSAR), k-nearest neighbour and pharmacophore approach. A suitable set of molecular descriptors was calculated and stepwise - partial component regression (SW-PCR) was employed to select the descriptors that resulted in the models with the best fit to the data. This study was performed with twenty two compounds using sphere exclusion algorithm method for the division of the data set into training and test set. The statistically significant 2D QSAR model having r(2) = 0.8407 and q(2) = 0.7395 with pred_r(2) = 0.7971 was developed by stepwise-partial component regression (SW-PCR) and best Group based QSAR model having R(2) = 0.8132 and Q(2) = 0.6804 with pred_r(2) = 0.7661 was developed by SW-PCR. The analyzed k-nearest neighbour MFA model revealed a good fit, having q(2) value of 0.7635. The predictive power of the model generated was validated using a test set molecules with pred _r(2) value of 0.7314. The generated k-nearest neighbour models suggest that steric and electrostatic interactions play an important role in describing the variation in binding affinity. Additionally the pharmacophore model well corraborated with k-nearest neighbour studies as the contours of later were in good agreement with the 3D orientation of the pharmacophoric features. The present analysis has shown that the antihypertensive activity can be improved with the presence of specific steric substituent and electro-donating and electro-withdrawing groups nearby the pyridine moiety. The Pharmacophore information shows that the four features used were two AroC feature, one HAc, one AlaC features. The structural variations in the molecular fields at particular regions in the space provide underlying structural requirements and 3D-QSAR models generated give good predictive ability and aid in the design of potent antihypertensive activity.