Department of Chemistry, University of Southern California , 3620 McClintock Avenue, Los Angeles, California 90089, United States.
J Phys Chem B. 2017 Jul 20;121(28):6831-6840. doi: 10.1021/acs.jpcb.7b04562. Epub 2017 Jul 5.
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 (k and K) 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.
丙型肝炎病毒（HCV）目前在全球范围内影响着数百万人。针对 HCV 的主要药物类别之一是抑制多蛋白链的 NS3/4A 蛋白酶。由于高突变率导致出现几种遗传相关的准种，这些药物的疗效受到严重限制。药物耐药性的分子机制通常是从结构研究和结合自由能推断出来的。然而，预测新的突变需要评估药物的结合自由能以及天然底物的参数（k 和 K）。活力值为研究和预测对抑制剂产生耐药性的突变提供了一种很好的方法。成功的突变应该只影响药物的结合，而不影响催化活性和天然底物的结合。在本文中，我们计算了四种已知药物抑制剂的活力值，这些抑制剂要么正在使用中，要么正在临床试验中，通过相关的 PDLD/S-LRA 方法评估结合自由能，通过 EVB 方法评估活化能垒。还讨论了与耐药性相关的分子细节。我们表明，我们的计算能够很好地重现与实验观察值相对应的催化效应和结合自由能。重要的是，以前的计算方法无法完成这项任务。活力值的趋势与实验结果一致。最后，我们计算了那些尚未进行实验研究或未报道某些抑制剂的突变的活力值。
