Identification of 13 Guanidinobenzoyl- or Aminidinobenzoyl-Containing Drugs to Potentially Inhibit TMPRSS2 for COVID-19 Treatment

Abstract

Positively charged groups that mimic arginine or lysine in a natural substrate of trypsin are necessary for drugs to inhibit the trypsin-like serine protease TMPRSS2 that is involved in the viral entry and spread of coronaviruses, including SARS-CoV-2. Based on this assumption, we identified a set of 13 approved or clinically investigational drugs with positively charged guanidinobenzoyl and/or aminidinobenzoyl groups, including the experimentally verified TMPRSS2 inhibitors Camostat and Nafamostat. Molecular docking using the C-I-TASSER-predicted TMPRSS2 catalytic domain model suggested that the guanidinobenzoyl or aminidinobenzoyl group in all the drugs could form putative salt bridge interactions with the side-chain carboxyl group of Asp435 located in the S1 pocket of TMPRSS2. Molecular dynamics simulations further revealed the high stability of the putative salt bridge interactions over long-time (100 ns) simulations. The molecular mechanics/generalized Born surface area-binding free energy assessment and per-residue energy decomposition analysis also supported the strong binding interactions between TMPRSS2 and the proposed drugs. These results suggest that the proposed compounds, in addition to Camostat and Nafamostat, could be effective TMPRSS2 inhibitors for COVID-19 treatment by occupying the S1 pocket with the hallmark positively charged groups.

Uncovering the mechanism of resveratrol in the treatment of diabetic kidney disease based on network pharmacology, molecular docking, and experimental validation

“…To further explore the specific binding sites where RES plays the above roles, we performed molecular docking validation. Generally, results of molecular docking are mainly evaluated by minimum binding free energy (Delta G) [ 39 ]. The lower the binding energy is, the less energy is required for the drug molecule to bind with the target, and it indicates a greater binding possibility and stability [ 40 , 41 ].…”

Review of Developments in Combating COVID-19 by Vaccines, Inhibitors, Radiations, and Nonthermal Plasma

“…The superimposition of previously published SARS-CoV-2 3CL-pro structures with bound GC376 is shown in Figure 3 d. N3, formerly known as the Michael acceptor inhibitor, was created with a computer-aided method. N3 has shown significant antiviral efficacy against infectious bronchitis viruses in an animal model and can selectively inhibit the Mopar of numerous coronaviruses, including SARS-CoV and MERS-CoV [ 56 , 57 , 58 ]. SARS-CoV-2 3CLpro was demonstrated to establish a covalent link with N3, acting as an irreversible inhibitor of SARS-CoV and MERS-CoV 3CLpro.…”

Current Potential Therapeutic Approaches against SARS-CoV-2: A Review

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