Effective treatment or vaccine is not yet available for combating SARS coronavirus 2 (SARS-CoV-2) that caused the COVID-19 pandemic. Recent studies showed that two drugs, Camostat and Nafamostat, might be repurposed to treat COVID-19 by inhibiting human TMPRSS2 required for proteolytic activation of viral spike (S) glycoprotein. However, their molecular mechanisms of pharmacological action remain unclear. Here, we perform molecular dynamics simulations to investigate their native binding sites on TMPRSS2. We revealed that both drugs could spontaneously and stably bind to the TMPRSS2 catalytic center, and thereby inhibit its proteolytic processing of the S protein. Also, we found that Nafamostat is more specific than Camostat for binding to the catalytic center, consistent with reported observation that Nafamostat blocks the SARS-CoV-2 infection at a lower concentration. Thus, this study provides mechanistic insights into the Camostat and Nafamostat inhibition of the SARS-CoV-2 infection, and offers useful information for COVID-19 drug development.

中文翻译：

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潜在的 COVID-19 药物（Camostat 和 Nafamostat）与人丝氨酸蛋白酶 TMPRSS2 自发结合


目前尚无有效的治疗方法或疫苗来对抗引起 COVID-19 大流行的 SARS 冠状病毒 2 (SARS-CoV-2)。最近的研究表明，Camostat 和 Nafamostat 两种药物可能通过抑制病毒刺突 (S) 糖蛋白蛋白水解激活所需的人 TMPRSS2 来重新用于治疗 COVID-19。然而，它们的药理作用的分子机制仍不清楚。在这里，我们进行分子动力学模拟来研究它们在 TMPRSS2 上的天然结合位点。我们发现这两种药物都能自发且稳定地结合到 TMPRSS2 催化中心，从而抑制其对 S 蛋白的蛋白水解过程。此外，我们发现 Nafamostat 比 Camostat 与催化中心的结合更具特异性，这与报道的 Nafamostat 在较低浓度下阻断 SARS-CoV-2 感染的观察结果一致。因此，这项研究提供了卡莫司他和 Nafamostat 抑制 SARS-CoV-2 感染的机制见解，并为 COVID-19 药物开发提供了有用的信息。