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Spontaneous Binding of Potential COVID-19 Drugs to Human Serine Protease TMPRSS2

preprint
submitted on 05.10.2020 and posted on 06.10.2020 by Haixia Zhu, Wenhao Du, Menghua Song, Qing Liu, Andreas Herrmann, Qiang Huang
Effective treatment or vaccine is not yet available for combating SARS coronavirus 2 (SARSCoV-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.

History

Email Address of Submitting Author

huangqiang@fudan.edu.cn

Institution

Fudan University, School of Life Sciences

Country

China

ORCID For Submitting Author

0000-0001-5238-1704

Declaration of Conflict of Interest

The authors declare that they have no competing interests.

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