Insight into the Structural Requirements of Narlaprevir-Type Inhibitors of NS3/NS4A Protease Based on HQSAR and Molecular Field Analyses

Jingyu      Zhu; Youyong      Li; Huidong      Yu; Liling      Zhang; Xinliang      Mao; Tingjun      Hou

Abstract

In the life cycle of hepatitis C virus (HCV), NS3/NS4A protease has been proved to play a vital role in the replication of the HCV virus. Narlaprevir and its derivatives, the inhibitors of NS3/NS4A, would be potentially developed as important anti-HCV drugs in the future. In this study, quantitative structure-activity relationship (QSAR) analyses for 190 narlaprevir derivatives were conducted using comparative molecular field analysis (CoMFA), comparative molecular indices analysis (CoMSIA) and hologram quantitative structure–activity relationship (HQSAR) techniques. Both of the best CoMFA and HQSAR models showed statistical significance for the training set and good predictive accuracy for the test set, which strongly manifested the robustness of the CoMFA and HQSAR models. The CoMFA contour maps and the HQSAR contribution maps were both presented. Furthermore, based on the essential factors for ligand binding derived from the QSAR models, sixteen new derivatives were designed and some of them showed higher inhibitory activities confirmed by our models and molecular docking studies. General speaking, this study provides useful suggestions for the design of potential anti-HCV drugs.

Keywords: CoMFA, HCV, HQSAR, Inhibitor, Molecular Docking, Narlaprevir, NS3/NS4A Protease, QSAR, 3D-QSAR, hepatocellular carcinoma, substrate, binding affinities, life cycle