The hepatitis C virus (HCV)
infection is a primary cause of
chronic hepatitis which eventually progresses to
cirrhosis and in some instances might advance to
hepatocellular carcinoma. According to the WHO report, HCV infects 130-150 million people globally and every year 350,000 to 500,000 people die from hepatitis C virus
infection. Great achievement has been made in viral treatment evolution, after the development of HCV NS3/4A
protease inhibitor (
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 employed a series of computational strategies to analyze the binding of
antiviral drug,
Boceprevir to HCV NS3/4A
protease mutants. Our results clearly demonstrate that the point mutations (V36M, T54S and R155K) in
protease are associated with lowering of its binding affinity with
Boceprevir. 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 reside 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 order to combat
Boceprevir resistance, renovation of binding interactions 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.