Virtual screening and drug likeness prediction of new potent TMPRSS2 inhibitors as a potential treatment of COVID-19

Abstract

Transmembrane serine protease 2 (TMPRSS2) is a human protease which plays an important role in the viral life cycle. This enzyme cleaves the spike protein required for Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) viral entry at the host cell. TMPRSS2 inhibitors might limit SARS-CoV-2 infection in the respiratory tract. This work aims at identifying new potent TMPRSS2 inhibitors for anti-SARS CoV-2 drug research. Indeed, Structure-Based Virtual Screening (SBVS) of 13 521 analog compounds to 4-carbamimidamidobenzoic acid,a potent TMPRSS2 inhibitor, was undertaken using FlexX program. Then, the top ranked 1000 compounds were re-scored using Glide Extra Precision (XP) and their binding mode into TMPRSS2 binding site was further analyzed in order to eliminate false positive ones. Finally, drug likeness and toxicity properties of the most promising inhibitors were predicted. Out of these, compounds S1 and S2 showed a higher TMPRSS2 inhibitory potency than that of GBS, the reference molecule. They also were predicted to occupy the entire TMPRSS2 binding site making a rational number of interactions. Still more remarkably, these two compounds were also predicted to have satisfying drug likeness properties, indicating that they might be promising lead compounds for further anti-SARS CoV-2 drug research.