Molecular mechanism of SARS-CoV-2 cell entry inhibition via TMPRSS2 by Camostat and Nafamostat mesylate
This article has been Reviewed by the following groups
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
- Evaluated articles (ScreenIT)
Abstract
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.
Article activity feed
-
SciScore for 10.1101/2020.07.21.214098: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources We used scipy’s [42] curve fitting algorithms to extract the IC50 with error estimates. scipy’ssuggested: NoneMolecular dynamics simulations: MD simulations were run with OpenMM 7.4.0 [43] using the CHARMM 36 force field (2019 version) [44] OpenMMsuggested: (OpenMM, RRID:SCR_000436)Camostat and nafamostat structures were taken from PubChem [45] with PubChem CIDs 4413 PubChemsuggested: (PubChem, RRID:SCR_004284)The latter are approximated using the matrix logarithm approximation of scipy [42] to compute the transition rate matrix R from the transition probability matrix T using the definition … SciScore for 10.1101/2020.07.21.214098: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources We used scipy’s [42] curve fitting algorithms to extract the IC50 with error estimates. scipy’ssuggested: NoneMolecular dynamics simulations: MD simulations were run with OpenMM 7.4.0 [43] using the CHARMM 36 force field (2019 version) [44] OpenMMsuggested: (OpenMM, RRID:SCR_000436)Camostat and nafamostat structures were taken from PubChem [45] with PubChem CIDs 4413 PubChemsuggested: (PubChem, RRID:SCR_004284)The latter are approximated using the matrix logarithm approximation of scipy [42] to compute the transition rate matrix R from the transition probability matrix T using the definition T = exp(Rτ) with the lag time τ. scipysuggested: (SciPy, RRID:SCR_008058)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
-
