Molecular Modeling Approach of Serine Protease NS3-4A Genotype 3a as a Potential Drug Target of Hepatitis C Virus: Homology Modeling and Virtual Screening Study

Abstract

Hepatitis C Virus (HCV), affecting millions of people worldwide, is the leading cause of liver disorder, cirrhosis, and hepatocellular carcinoma. HCV is genetically diverse having seven genotypes and several subtypes that are predominant in different regions of the globe. The HCV NS3/4A protease is a major therapeutic target for HCV with various direct acting FDA approved antivirals, and several in clinical development. However, available protease inhibitors (PIs) have lower potency against HCV genotype 3, prevalent in South Asia. Lack of structural data limited our ability to recognize loss of inhibitory potential of PIs. In this study, we attempted to get structural insight of protease GT3 by modeling techniques. The incumbent computational tools were utilized to understand and explore interactions of HCV GT3 receptor with the potential inhibitors after virtual screening of in-house synthesized compound library. The molecular dynamics and pharmacological studies revealed compound Li_PIS_19 exhibiting the favorable binding and better pharmacokinetics properties that may be considered as the most promising compound against HCV GT3 protease.