Targeting HCV polymerase: a structural and dynamic perspective into the mechanism of selective covalent inhibition.

: Concerns have been raised over the emerging pandemic status of hepatitis C virus (HCV). Current available drugs lack specificity, stability and potency. The HCV NS5B RNA-dependent RNA polymerase (RdRp) is a vital component in viral replication and is often targeted in antiviral therapies. Recent experimental procedures have led to the discovery of a novel covalent RdRp inhibitor, compound 47, which selectively targets cysteine 366 of the HCV RdRp and exhibits promising pharmacokinetic outcomes. Selective covalent inhibition of HCV is, however, a highly neglected subject in the literature, that is reinforced by the lack of efficient structure-based drug design protocols. In this paper, an atomistic insight into a novel selective approach to inhibit HCV RdRp is provided. /: Covalent molecular dynamic analyses revealed the inhibitory mechanism of compound 47 on the RdRp. Inhibitor binding induced distinctive internal movements resulting in the disruption of normal physiological interdomain interactions. : Compound 47 stimulates reorganization of key protein elements required for RNA transcription, thus hampering viral replication as well as disrupting the overall conformation of HCV. This study will open new lines of approach for the design of novel selective inhibitors against HCV as well as other viral families.