Molecular Docking and Molecular Dynamic Simulation: Insight int o the Difference in Binding of HCV NS3/4A Macrocyclic Inhibitors to Genotypes 1b and 4a

Abstract

HCV NS3 protease domain has been attractive site for inhibition by several direct-acting antiviral drugs. A great success was achieved in treatment of HCV genotype 1 but HCV genotype 4a dominant in Egypt is resistant for many of these drugs while sensitive to some and the causes of these observations have not been deeply investigated. So we constructed a 3D model of HCV NS3 of genotype 4a using HCV NS3 genotype 1b as a template PDB (1DY9) and after close inspection of differences between the model and the template that would alter the drug susceptibility in HCV genotype 4a we performed a comparative computational docking study of Simeprevir, Vaniprevir, and Paritaprevir in NS3 protease domain of both the genotypes. The result of our study successfully explains the difference in response to treatment by HCV NS3 protease inhibitors drugs for both genotypes. It shows that Simeprevir retains its activity in both genotypes but Paritaprevir loses a significant part of its activity that cannot be used alone in HCV genotype 4a, while Vaniprevir remarkably loses its activity that cannot be used in HCV genotype 4a at all. Dynamic simulation of the 3D model of HCV NS3 of genotype 4a was done to augment the docking result. Then a series of some modified inhibitors were virtually screened against our model and this would open a new era to use structure based drug design in developing new drugs that act preferentially in treatment of HCV genotype 4a or other genotypes dominant in developing countries.