Understanding the Molecular Mechanism of Synergistic Inhibition in the Hepatitis C Virus (HCV) Polymerase via a Computational Investigation of Protein Dynamics

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A major challenge of treating HCV infection is the emergence of resistance to current treatment regimens. An approach to reducing the rate of drug resistance is to increase the inhibitory effects of allosteric inhibitors by using them in combination to target the HCV polymerase (NS5B). Although recent biochemical studies show the use of multiple allosteric inhibitors has a synergistic inhibitory effect on the HCV polymerase, the mechanism by which this synergistic inhibition occurs still has not been clearly elucidated. To garner insight into the mechanism of synergistic inhibition of NS5B, we employ molecular dynamics (MD) simulations of the enzyme simultaneously bound to two allosteric ligands. In concert with covariance and principal component analyses, the data from MD simulations allow us to compare specific structural and dynamic properties of the free and ligand-bound protein. Understanding the molecular mechanism that mediate synergistic inhibition in NS5B may allow us to optimize the inhibitory activity of these compounds against the enzyme. In addition, these studies can provide fundamental insights into how ligand binding regulates protein function. Such information has direct applications in the areas of drug discovery, regulation of metabolic pathways and other signal transduction processes.