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

Journal of Biomolecular Structure & Dynamics
Mukhtar Oluwaseun IdrisOlanrewaju Ayodeji Durojaye

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 homology-modelled 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...Continue Reading

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Citations

Oct 8, 2020·Memórias do Instituto Oswaldo Cruz·Mario Roberto SengerFloriano Paes Silva-Junior
May 8, 2021·Methods : a Companion to Methods in Enzymology·Ankur GuptaShailendra K Saxena
May 17, 2021·Bioorganic & Medicinal Chemistry·Leandro Rocha SilvaEdeildo Ferreira da Silva-Júnior
Sep 9, 2021·Journal of Biomolecular Structure & Dynamics·Erman Salih IstifliBektas Tepe
Oct 30, 2021·Frontiers in Chemistry·Mehdi MahmudpourMaryam Farrokhnia

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Methods Mentioned

BETA
Profiler
MDS
PCA

Software Mentioned

ZINCPharmer
Autodock Vina
GalaxyRefine
Pharmer
ERRAT
MODEL
MMPBSA
BINDSURF Blind Docking Server
Visual Molecular Dynamics ( VMD )
SWISS

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