COMPUTATIONAL ANALYSIS OF THE MOLECULAR PRINCIPLE BEHIND BOCEPREVIR RESISTANCE DUE TO MUTATION IN HEPATITIS CNS3/4A PEOTEASE AND THE DEVELOPMENT OF NEW NS3/4A PROTEASE INHIBITOR

Abstract

The hepatitis C virus (HCV) Infection is a primary cause of chronic hepatitis that eventually progresses to cirrhosis and in some instances might advance to Hepatocellular carcinoma. According to the WHO report, HCV infects 130–150 millions people globally and every year 350000 to 500000 people die from hepatitis C virus infection. Great achievement has been made in viral treatment evolution, after the development of HCV NS3/4A protease inhibitors (Boceprevir). However, efficacy of boceprevir is compromised by the emergence of drug resistant variants. The molecular principle behind drug resistance of the protease mutants such as (V36M, T54S and R155K) is still poorly understood. Therefore in this study, we have employed series of computational strategies such as molecular dynamics simulation, solvent accessibility variation, the salt bridge interactions analysis, substrate envelope analysis and binding pocket analysis to analyze the binding of antiviral drug, boceprevir to HCV NS3/4A protease mutants. Our results clearly demonstrate that the point mutation (V36M, T54S and R155K) in protease is associated with lowering of binding affinity between of binding between boceprevir and protease. Exhaustive analysis of the simulated boceprevir bound wild and mutant complexes revealed variations in hydrophobic interactions, hydrogen bond occupancy and salt bridge interactions. Also, substrate envelope analysis scrutinized that the studied mutations resides outside the substrate envelope which may affect the boceprevir affinity towards HCV protease but not the protease enzymatic activity. Furthermore, structural analyses of the binding site volume and flexibility show impairment in flexibility and stability of the binding site residues in mutant structures. In the last of the report, we also identify the common inhibitor of the wild and mutant proteases by parallel virtual screening through combinatorial libraries which are constructed based on boceprevir scaffold. In order to combat boceprevir resistance, renovation of binding interaction between the Drug and protease may be valuable. The structural insight from this study reveals the mechanism of the boceprevir resistance and the results can be valuable for the design of new PIs with improved efficiency.