QSAR and pharmacophore modeling of indole-based C-3 pyridone compounds as HCV NS5B polymerase inhibitors utilizing computed molecular descriptors

Abstract

A series of indole-based C-3 pyridone compounds active against Hepatitis C virus as HCV NS5B polymerase inhibitors have been explored under the framework of quantitative structure–activity relationships (QSARs) and pharmacophore modeling in the present article. QSAR models were developed by considering various kinds of theoretical molecular descriptors including constitutional and geometrical, topological, functional group, and atom-centered fragments indices computed solely from the structure of indole-based C-3 pyridone compounds utilizing stepwise forward−backward variable selections incorporated in multiple linear regression (MLR) methods. MLR shows that topological indices can contribute the maximum impact on biological activity obtained in terms of model quality parameters, such as R 2 = 0.946, $$ Q_{\text{Loo}}^{2} $$ = 0.883, and $$ R_{\text{pred}}^{2} $$ = 0.642, respectively. Constitutional and geometrical-based model can produce R 2 = 0.849, $$ Q_{\text{Loo}}^{2} $$ = 0.776, and $$ R_{\text{pred}}^{2} $$ = 0.623, respectively; whereas, model utilizing functional group and atom-centered fragments indices can contribute R 2 = 0.885, $$ Q_{\text{Loo}}^{2} $$ = 0.812, and $$ R_{\text{pred}}^{2} $$ = 0.612, respectively. Prediction of essential structural features is strongly achieved by introducing pharmacophore modeling of these highly active congeners which showed that more number of hydrogen bonding interactions between the substituents associated to the various points of diversity of the indole nucleus including N-1, C-2, and C-3 aromatic groups with the HCV NS5B polymerase target may enhance the biological activities in this congeneric ligands.