Structural insights into mode of actions of novel substituted 4- and 6-azaindole-3-carboxamides analogs as renin inhibitors: molecular modeling studies

Abstract

A series of substituted 4- and 6-azaindole-3-carboxamides derivatives displaying potent activities against renin inhibitors were selected to establish quantitative structure–activity relationships using two dimensional, k-nearest neighbor (kNN), and pharmacophore analysis methods. The QSAR models of the substituted 4- and 6-azaindole-3-carboxamides derivatives have been developed by partial least square (PLS) methodology coupled genetic algorithm, simulated annealing and stepwise, for the purpose of an effective comparison and some interesting results are obtained. The statistically best significant 2D-QSAR model having r2 = 0.8644 and q2 = 0.7630 with pred_r2 = 0.8009 was developed by GA-PLS method with the descriptors like positive contribution of SsCH3E-index, T_C_F_5 T_2_Cl_1, SssOE-index. The result model of the QSAR study suggests the methyl, methoxy, fluorine, chlorine substituents in the nucleus will increase the binding affinity of 4- and 6-azaindole-3-carboxamides derivatives and positive contribution of descriptors illustrates that increase in branching and presence of methyl, methoxy, fluorine, chlorine is favorable for renin inhibitory activity. Further analysis using kNN methodology with GA-PLS, SA-PLS, and SW-PLS was used for building the QSAR models. The most significant model is having internal predictivity 74 % (q2 = 0.7408) and external predictivity 78.3 % (pred_r2 = 0.7837). Model showed that electrostatic (E_886, E_561) steric (S_522), and hydrophobic (H_1136) interactions play important role in determining renin inhibitory activity. The pharmacophore analysis of the molecules demonstrated that the AroC feature (aromatic), hydrogen-bond donor (HDr), hydrogen-bond acceptor (HAc), and PosC features are important pharmacophore contours favorable for these activities. The information obtained from 2D descriptors, three-dimensional contour maps and pharmacophore approach can be used for further design of substituted 4- and 6-azaindole-3-carboxamides analogs as renin inhibitors.