Homology Modeling of TMPRSS2 Yields Candidate Drugs That May Inhibit Entry of SARS-CoV-2 into Human Cells

Abstract

The most rapid path to discovering treatment options for the novel coronavirus SARS-CoV-2 is to find existing medications that are active against the virus. We have focused on identifying repurposing candidates for the transmembrane serine protease family member II (TMPRSS2), which is critical for entry of coronaviruses into cells. Using known 3D structures of close homologs, we created seven homology models. We also identified a set of serine protease inhibitor drugs, generated several conformations of each, and docked them into our models. We used three known chemical (non-drug) inhibitors and one validated inhibitor of TMPRSS2 in MERS as benchmark compounds and found six compounds with predicted high binding affinity in the range of the known inhibitors. We also showed that a previously published weak inhibitor, Camostat, had a significantly lower binding score than our six compounds. All six compounds are anticoagulants with significant and potentially dangerous clinical effects and side effects. Nonetheless, if these compounds significantly inhibit SARS-CoV-2 infection, they could represent a potentially useful clinical tool.

Molecular mechanism of inhibiting the SARS-CoV-2 cell entry facilitator TMPRSS2 with camostat and nafamostat

“…3F). 40 In this orientation, the guanidinium head mainly interacts with Glu299, with the drug reactive center slightly displaced from the oxyanion hole, while the "forward" orientation ( Fig. 3E) keeps the amidinium head mainly nearby Val280, with the ester center well positioned for the reaction (Fig.…”

“…[35][36][37][38][39] Here, we initialize our simulations with recent homology models of the TMPRSS2 protease domain and with camostat/ nafamostat docked to them. 40 Trypsins adopt a common fold and share an active-site charge relay system whose structural requirements for catalytic activity are well understood; 41 we select our MD model consistent with these structural requirements. In particular, we focus on systems with Asp435 (substrate recognition) deprotonated and His296 (catalytic function) in a neutral form (N d protonated), as well as on the interactions of a charged lysine nearby the catalytic Asp345 ( Fig.…”

“…It is taken from ref. 40, model 3W94 is chosen based on precursive MD analyses that showed that 3W94 has the most stable catalytic triad conguration ( Fig. S1 and S2 †).…”

The anticoagulant nafamostat potently inhibits SARS-CoV-2 infectionin vitro: an existing drug with multiple possible therapeutic effects

“…S1d). 6 Therefore, nafamostat mesylate was 10-fold more potent than camostat mesylate. Furthermore, drug concentrations required for fusion inhibition in lung epithelial cells were 10-fold lower than those required for inhibition using 293FT cells ( Fig.…”

“…Various computational approaches have recently been applied to find existing medications targeting TMPRSS2 6,7 . Consistent with our results, these studies ranked nafamostat mesylate significantly higher than camostat mesylate.…”