The Molecular Simulation Research On The Interaction Between HCV NS5B Polymerase And Its Inhibitors

Despite the discovery of the hepatitis C virus (HCV) more than 20 years, Hepatitis c has attracted a global attention by the serious social and public health problems. However, the inhibitors, entered into the clinical trials, take the performance of resistance. So far there have still been no vaccines and drugs on the market, which is in the imminent situation. NS5B polymerase has become one of the most important targets in drug development on HCV. Many inhibitors have been discoved and developed. Although most of the inhibitors have good broad-spectrum activity, many of them have to give up because of the resistance. Therefore, it is important and valuable to research on the mutation mechanism for designing a new kind of inhibitors. In this paper, two works about the combination of the inhibitors with HCV NS5B polymerase was studied by the molecular dynamics simulation method:1) The first research is mainly about the new inhibitor PF-00868554, which combined with theâ…£active pocket of NS5B polymerase, being entered into the clinical trials. When the mutation of 423 happened, the shape of the pocket is changed. This leads the weak interaction between inhibitor and polymerase. It is a new way to design for the second generation of inhibitors with the theoretical guidance on the molecular level.2) At the second study, the work mainly aimed at inhibitor NN2, which combined with theâ…¡active pocket of NS5B polymerase. The mutation of M414T made the steric clash smaller, which result in the weak combnination with the inhibitor NN2. The mutation of W448H increased the electrostatic interaction. Because of this reason, the four rings of inhibitor NN2 are no longer coplanar, which cause the combination between inhibitor NN2 and NS5B polymerase abate.