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首页> 外文期刊>The journal of physical chemistry, B. Condensed matter, materials, surfaces, interfaces & biophysical >Exploring the Drug Resistance of HCV Protease
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Exploring the Drug Resistance of HCV Protease

机译：探索HCV蛋白酶的耐药性

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摘要

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(cat) and K-M) 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.
机译：丙型肝炎病毒（HCV）目前影响全球数百万人。针对HCV的主要药物之一抑制了多蛋白链的NS3 / 4A蛋白酶。由于几种转基因Quasispecies导致几种突变率，这些药物的疗效受到严重限制。耐药性的分子机制经常从结构研究中推导和结合自由能。然而，新突变的预测需要评估药物的结合自由能以及天然基质的参数（K（猫）和K-M）。活力值提供了一种良好的方法来研究和预测对抑制剂抗性的突变。成功的突变仅影响药物的结合而不是天然基质的催化活性和结合。在本文中，我们已经计算了目前在使用或临床试验中的四种已知药物抑制剂的活力值，通过EVB方法评估了通过相关的PDLD / S-LRA方法和活化屏障的结合可加速度。还讨论了与电阻有关的分子细节。我们表明我们的计算能够与相应的观察值良好的一致性再现催化作用和结合可自由能量。重要的是，以前的计算方法无法实现这项任务。活力值的趋势符合实验结果。最后，我们计算未经实验研究的突变的生命力值，或者为一些抑制剂报告。

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