Understanding Allosteric Inhibition in Ligand AG6 Bound to NS5B using Molecular Dynamic Simulations

Abstract

Abstract: Hepatitis C Virus (HCV) is a major health concern; the virus infects 270-300 million people worldwide. The large number of people infected has spurred efforts to identify small molecules that may be effective in treating HCV infection. One of the targeted viral enzymes in these efforts is the viral RNA Dependent RNA polymerase (NS5B) that plays a vital role in replicating the HCV genome. Several allosteric inhibitors are known to bind to NS5B in the thumb, fingers and palm domains of the enzyme. Our goal is to understand the mechanism of allosteric inhibition in NS5B using molecular dynamic simulations. We are particularly interested in ligand AG6 that has been shown to bind to the fingers domain. Relatively few allosteric inhibitors are known to bind to this region of the protein. Studying allosteric inhibiton involving this uncommon binding site has led to new insights into the mechanisms of allostery in NS5B. Moreover, crystallographic data indicate that NS5B can bind simultaneously to AG6 and another allosteric inhibitor in the thumb domain. This has given us an opportunity to learn what mechanisms underlie synergistic binding of multiple allosteric inhibitors to the enzyme. We used molecular dynamic simulations to understand how changes in the free energy landscape of NS5B mediate the allosteric effects of inhibitor binding.