Computer-aided screening for potential TMPRSS2 inhibitors: a combination of pharmacophore modeling, molecular docking and molecular dynamics simulation approaches

Abstract

Transmembrane serine protease 2 (TMPRSS2) has been established as one of the host proteins that facilitate entry of coronaviruses into host cells. One of the approaches often employed towards preventing the entry and proliferation of viruses is computer-aided inhibition studies to identify potent compounds that can inhibit activity of viral targets in the host through binding at the active site. In this study, we developed a pharmacophore model of reportedly potent drugs against severe acute respiratory syndrome coronaviruses 1 and 2 (SARS-CoV-1 and-2). The model was used to screen the ZINC database for commercially available compounds having similar features with the experimentally tested drugs. The top 3000 compounds retrieved were docked into the active sites of a homologymodelled TMPRSS2. Docking scores of the top binders were validated and the top-ranked compounds were subjected to ADME, Lipinski's and medicinal Chemistry property predictions for druglikeness analyses. Two lead compounds, ZINC64606047 and ZINC05296775, were identified having binding affinities higher than those of the reference inhibitors, favorable interactions with TMPRSS2 active site residues and good ADME and medicinal chemistry properties. Molecular dynamics simulation was used to assess the stability and dynamics of the interactions of these compounds with TMPRSS2. Binding free energy and contribution energy evaluations were determined using MMPBSA method. Analyses of the trajectory dynamics collectively established further that the lead compounds bound and interacted stably with active site residues of TMPRSS2. Nonetheless, experimental studies are needed to further assess the potentials of these compounds as possible therapeutics against coronaviruses.

Pharmacoinformatics-based identification of transmembrane protease serine-2 inhibitors from Morus Alba as SARS-CoV-2 cell entry inhibitors

“…Idris et al [ 65 ] were performed the pharmacophore-based virtual screening of the ZINC database against TMPRSS2 target. After molecular docking and in-silico pharmacokinetic analyses, they were found two promising molecules.…”

“…In each and every molecule, a small number of frames were also found without any hydrogen bonds but those frames were remained stabled with non-hydrogen bond interactions. Idris et al [65] were performed the pharmacophorebased virtual screening of the ZINC database against TMPRSS2 target. After molecular docking and in-silico pharmacokinetic analyses, they were found two promising molecules.…”

TMPRSS2 and ADAM17 interactions with ACE2 complexed with SARS-CoV-2 and B0AT1 putatively in intestine, cardiomyocytes, and kidney

“…SARS-CoV-2 infectivity in human cells can be inhibited by Camostat, Nafamostat and several other experimental small molecules[49-52]. These strongly interact with TMPRSS2’s active site pocket involving the catalytic triad of H296, S441 and D345 and substrate recognition residues D435, S460 and G462 [49, 50, 64, 79, 80]. Reported molecular dynamics docking binding energies for this structure of TMPRSS2 include −7.20 kcal/mol [51] or −7.94 kcal/mol [50] for Camostat mesylate, and −7.21 Kcal/mol [51] or −8.20 kcal/mol [50] for Nafamostat, and the highest molecular docking score for experimental anti-SARS-CoV-2 compound NPC306344 [64].…”

COVID-19: molecular targets, drug repurposing and new avenues for drug discovery

“…(65,138) Potential TMPRSS2 blockers include some serine protease inhibitors [e.g., camostat mesylate (23)], commercially available compounds [e. g., ZINC64606047 (24), 3-[[5-(3-fluorophenyl)pyrimidin-2-yl]amino~(N)-(4-methyl phenyl)benzamide]] and natural products [e.g., withanone (25)]. (65,139,140,141) In the absence of exogenous or membrane-bound proteases (e g. TMPRSS2) to promote SARS-CoVs infection on cells' surface, the virus can also be internalised via endocytosis, also known as "late pathway". (59) This process comprises several factors that operate in a sequential and partially overlapping fashion.…”

“… 65 , 138 Potential TMPRSS2 blockers include some serine protease inhibitors [e.g., camostat mesylate (23)], commercially available compounds [e. g., ZINC64606047 (24), 3-[[5-(3-fluorophenyl)pyrimidin-2-yl]amino~(N)-(4-methyl phenyl)benzamide]] and natural products [e.g., withanone (25)]. 65 , 139 , 140 , 141 …”