tetano
Editor, Senior Moderator
Comput Struct Biotechnol J
. 2020 Dec 28;19:467-476.
doi: 10.1016/j.csbj.2020.12.035. eCollection 2021.
Spontaneous binding of potential COVID-19 drugs (Camostat and Nafamostat) to human serine protease TMPRSS2
Haixia Zhu[SUP] 1 [/SUP], Wenhao Du[SUP] 1 [/SUP], Menghua Song[SUP] 1 [/SUP], Qing Liu[SUP] 2 [/SUP], Andreas Herrmann[SUP] 3 [/SUP], Qiang Huang[SUP] 1 4 [/SUP]
Affiliations
Abstract
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.
Keywords: COVID-19; Drug action; SARS-CoV-2; Spontaneous binding simulation; TMPRSS2.
. 2020 Dec 28;19:467-476.
doi: 10.1016/j.csbj.2020.12.035. eCollection 2021.
Spontaneous binding of potential COVID-19 drugs (Camostat and Nafamostat) to human serine protease TMPRSS2
Haixia Zhu[SUP] 1 [/SUP], Wenhao Du[SUP] 1 [/SUP], Menghua Song[SUP] 1 [/SUP], Qing Liu[SUP] 2 [/SUP], Andreas Herrmann[SUP] 3 [/SUP], Qiang Huang[SUP] 1 4 [/SUP]
Affiliations
- PMID: 33505639
- PMCID: PMC7809394
- DOI: 10.1016/j.csbj.2020.12.035
Abstract
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.
Keywords: COVID-19; Drug action; SARS-CoV-2; Spontaneous binding simulation; TMPRSS2.