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submitted on 05.10.2020 and posted on 06.10.2020by 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.