Author: Hempel, Tim; Raich, LluÃs; Olsson, Simon; Azouz, Nurit P.; Klingler, Andrea M.; Rothenberg, Marc E.; Noé, Frank
Title: Molecular mechanism of SARS-CoV-2 cell entry inhibition via TMPRSS2 by Camostat and Nafamostat mesylate Cord-id: hspl0q4u Document date: 2020_7_21
ID: hspl0q4u
Snippet: The entry of the coronavirus SARS-CoV-2 into human 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 the hypothesis that both drugs act by inhibiting the human protein TMPRSS2. 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 280
Document: The entry of the coronavirus SARS-CoV-2 into human 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 the hypothesis that both drugs act by inhibiting the human protein TMPRSS2. 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 280 microseconds of all-atom molecular dynamics (MD) and Markov modeling. We describe the binding mode of both drugs with TMPRSS2 in a Michaelis complex (MC) state preceding the formation of a long-lived covalent inhibitory state. We find that nafamostat to has a higher MC population, which in turn leads to the more frequent formation of the covalent complex and thus higher inhibition efficacy, as confirmed in vitro 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.
Search related documents:
Co phrase search for related documents- acid catalysis and active site: 1, 2
- acid catalysis and activity assay: 1
- acid catalysis and acute respiratory syndrome: 1, 2, 3
- acid catalysis and acute respiratory syndrome coronavirus: 1, 2, 3
- active form and acute respiratory syndrome: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25
- active form and acute respiratory syndrome coronavirus: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25
- active site and acute respiratory syndrome: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25
- active site and acute respiratory syndrome coronavirus: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25
- active site and acyl enzyme: 1, 2, 3
- active site and acyl enzyme intermediate: 1
- activity assay and acute respiratory syndrome: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25
- activity assay and acute respiratory syndrome coronavirus: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25
- acute respiratory syndrome and acyl enzyme: 1, 2
- acute respiratory syndrome and acyl enzyme intermediate: 1, 2
- acute respiratory syndrome and acyl enzyme intermediate hydrolysis: 1
- acute respiratory syndrome coronavirus and acyl enzyme: 1
- acute respiratory syndrome coronavirus and acyl enzyme intermediate: 1
Co phrase search for related documents, hyperlinks ordered by date