The Hepatitis C virus (HCV) NS3/4A protease is an important target for HCV therapy. Several HCV protease inhibitors have entered the market in recent years and even more are progressing in the clinic, among which is MK-5172, a next generation protease inhibitor developed by Merck that is currently under regulatory review for marketing approval. As with other anti-viral therapies such as those for HIV, a major challenge in HCV drug research is the emergence of drug-resistance. In this presentation, we will highlight our strategies in applying computational techniques to the investigation of resistance-associated variants (RAVs) conferred with MK-5172 and other HCV protease inhibitors (e.g., R155K, D168A, and A156T). Various approaches are explored, such as free energy calculations, energetics analysis and characterization of relevant conformational states. These studies provide a clear rationale for the effect of these RAVs on the binding of MK-5172, and offer structural insight into the mechanisms of drug resistance, which is invaluable in guiding future experimental design.

Insight into the mechanisms of resistance-associated variants of HCV NS3 protease binding to MK-5172: A computational study

251st National Meeting (2016)

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