Molecular mechanism of inhibiting the SARS-CoV-2 cell entry facilitator TMPRSS2 with camostat and nafamostat.
Molecular mechanism of inhibiting the SARS-CoV-2 cell entry facilitator TMPRSS2 with camostat and nafamostat.
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DOI：
10.1039/d0sc05064d
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发表时间：
2021-01-21
期刊：
影响因子：
8.4
通讯作者：
Noé F
中科院分区：
文献类型：
--
作者：
Hempel T;Raich L;Olsson S;Azouz NP;Klingler AM;Hoffmann M;Pöhlmann S;Rothenberg ME;Noé F
冠状病毒SARS-CoV-2进入人肺细胞可以被批准的药物卡莫他和那莫他抑制。本文采用实验与模拟相结合的方法对这些药物的分子机制进行了阐述。体外试验证实，这两种药物都能抑制人蛋白TMPRSS2，这是一种SARS-Cov-2刺突蛋白激活剂。由于没有可用的实验结构，我们通过330微秒的全原子分子动力学和马尔可夫建模来放松初始同源结构，建立了TMPRSS2平衡结构及其波动的模型。通过马尔可夫模型，我们描述了药物和卡莫司他代谢产物（GBPA）与TMPRSS2的结合过程，达到Michaelis复合物（MC）状态，然后形成长寿命的共价抑制状态。我们发现，与卡莫司他和GBPA相比，那莫司他具有更高的MC种群，这表明那莫司他更容易形成稳定的共价酶底物中间体，有效地解释了它的高效。该模型得到了我们体外实验的支持，并与以前的病毒细胞进入试验一致。我们的tmprss2药物结构被公开，以指导更有效和特异性抑制剂的设计。作者揭示了两种靶向人TMPRSS2蛋白的潜在COVID-19药物nafamostat和camostat的分子作用原理。
The entry of the coronavirus SARS-CoV-2 into human lung cells can be inhibited by the approved drugs camostat and nafamostat. Here we elucidate the molecular mechanism of these drugs by combining experiments and simulations. In vitro assays confirm that both drugs inhibit the human protein TMPRSS2, a SARS-Cov-2 spike protein activator. As no experimental structure is available, we provide a model of the TMPRSS2 equilibrium structure and its fluctuations by relaxing an initial homology structure with extensive 330 microseconds of all-atom molecular dynamics (MD) and Markov modeling. Through Markov modeling, we describe the binding process of both drugs and a metabolic product of camostat (GBPA) to TMPRSS2, reaching a Michaelis complex (MC) state, which precedes the formation of a long-lived covalent inhibitory state. We find that nafamostat has a higher MC population than camostat and GBPA, suggesting that nafamostat is more readily available to form the stable covalent enzyme–substrate intermediate, effectively explaining its high potency. This model is backed by our in vitro experiments and consistent with previous virus cell entry assays. Our TMPRSS2–drug structures are made public to guide the design of more potent and specific inhibitors. The authors unravel the molecular action principle of nafamostat and camostat, two potential COVID-19 drugs targeting the human protein TMPRSS2.
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