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J Phys Chem B. 2017 Jul 20;121(28):6831-6840. doi: 10.1021/acs.jpcb.7b04562. Epub 2017 Jul 5.

Exploring the Drug Resistance of HCV Protease.

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Department of Chemistry, University of Southern California , 3620 McClintock Avenue, Los Angeles, California 90089, United States.


Hepatitis C virus (HCV) currently affects several million people across the globe. One of the major classes of drugs against HCV inhibits the NS3/4A protease of the polyprotein chain. Efficacy of these drugs is severely limited due to the high mutation rate that results in several genetically related quasispecies. The molecular mechanism of drug resistance is frequently deduced from structural studies and binding free energies. However, prediction of new mutations requires the evaluation of both binding free energy of the drug as well as the parameters (kcat and KM) for the natural substrate. The vitality values offer a good approach to investigate and predict mutations that render resistance to the inhibitor. A successful mutation should only affect the binding of the drug and not the catalytic activity and binding of the natural substrate. In this article, we have calculated the vitality values for four known drug inhibitors that are either currently in use or in clinical trials, evaluating binding free energies by the relevant PDLD/S-LRA method and activation barriers by the EVB method. The molecular details pertaining to resistance are also discussed. We show that our calculations are able to reproduce the catalytic effects and binding free energies in a good agreement with the corresponding observed values. Importantly, previous computational approaches have not been able to achieve this task. The trend for the vitality values is in accordance with experimental findings. Finally, we calculate the vitality values for mutations that have either not been studied experimentally or reported for some inhibitors.

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