Exploring the P2 and P3 ligand binding features for Hepatitis C virus NS3 protease using some 3D QSAR techniques

Abstract

Several three-dimensional quantitative structure–activity relationship (3D-QSAR) models have been constructed using the comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and Catalyst pharmacophore feature building programs for a series of 26 truncated ketoacid inhibitors designed particularly for exploring the P2 and P3 binding pockets of HCV NS3 protease. The structures of these inhibitors were built from a structure template extracted from the crystal structure of HCV NS3 protease. The structures were aligned through docking each inhibitor into the NS3 active site using program GOLD. The best CoMSIA model was identified from the stepwise analysis results and the corresponding pharmacophore features derived were used for constructing a pharmacophore hypothesis by the Catalyst program. Pharmacophore features obtained by CoMFA and CoMSIA are found to be in accord with each other and are both mapped onto the molecular 5 K surface of NS3 active site. These pharmacophore features were also compared with those obtained by the Catalyst program and mapped onto the same NS3 molecular surface. The pharmacophore building process was also performed for 20 boronic acid based NS3 inhibitors characterized by a long hydrophobic side chain attached at position P2. This latter pharmacophore hypothesis built by the Catalyst program was also mapped onto the molecular surface of NS3 active site to define a second hydrophobic feature at position P2. The possibility of using the pharmacophore features mapped P2 and P3 binding pocket to design more potent depeptidized NS3 inhibitors was discussed.