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In Silico Screening of Novel TMPRSS2 Inhibitors for Treatment of COVID-19

COVID-19, a pandemic caused by the virus SARS-CoV-2, has spread globally, necessitating the search for antiviral compounds. Transmembrane protease serine 2 (TMPRSS2) is a cell surface protease that plays an essential role in SARS-CoV-2 infection. Therefore, researchers are searching for TMPRSS2 inhi...

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Autores principales: Wang, Shuo, Fang, Xuexun, Wang, Ye
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268035/
https://www.ncbi.nlm.nih.gov/pubmed/35807455
http://dx.doi.org/10.3390/molecules27134210
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author Wang, Shuo
Fang, Xuexun
Wang, Ye
author_facet Wang, Shuo
Fang, Xuexun
Wang, Ye
author_sort Wang, Shuo
collection PubMed
description COVID-19, a pandemic caused by the virus SARS-CoV-2, has spread globally, necessitating the search for antiviral compounds. Transmembrane protease serine 2 (TMPRSS2) is a cell surface protease that plays an essential role in SARS-CoV-2 infection. Therefore, researchers are searching for TMPRSS2 inhibitors that can be used for the treatment of COVID-19. As such, in this study, based on the crystal structure, we targeted the active site of TMPRSS2 for virtual screening of compounds in the FDA database. Then, we screened lumacaftor and ergotamine, which showed strong binding ability, using 100 ns molecular dynamics simulations to study the stability of the protein–ligand binding process, the flexibility of amino acid residues, and the formation of hydrogen bonds. Subsequently, we calculated the binding free energy of the protein–ligand complex by the MM-PBSA method. The results show that lumacaftor and ergotamine interact with residues around the TMPRSS2 active site, and reached equilibrium in the 100 ns molecular dynamics simulations. We think that lumacaftor and ergotamine, which we screened through in silico studies, can effectively inhibit the activity of TMPRSS2. Our findings provide a basis for subsequent in vitro experiments, having important implications for the development of effective anti-COVID-19 drugs.
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spelling pubmed-92680352022-07-09 In Silico Screening of Novel TMPRSS2 Inhibitors for Treatment of COVID-19 Wang, Shuo Fang, Xuexun Wang, Ye Molecules Article COVID-19, a pandemic caused by the virus SARS-CoV-2, has spread globally, necessitating the search for antiviral compounds. Transmembrane protease serine 2 (TMPRSS2) is a cell surface protease that plays an essential role in SARS-CoV-2 infection. Therefore, researchers are searching for TMPRSS2 inhibitors that can be used for the treatment of COVID-19. As such, in this study, based on the crystal structure, we targeted the active site of TMPRSS2 for virtual screening of compounds in the FDA database. Then, we screened lumacaftor and ergotamine, which showed strong binding ability, using 100 ns molecular dynamics simulations to study the stability of the protein–ligand binding process, the flexibility of amino acid residues, and the formation of hydrogen bonds. Subsequently, we calculated the binding free energy of the protein–ligand complex by the MM-PBSA method. The results show that lumacaftor and ergotamine interact with residues around the TMPRSS2 active site, and reached equilibrium in the 100 ns molecular dynamics simulations. We think that lumacaftor and ergotamine, which we screened through in silico studies, can effectively inhibit the activity of TMPRSS2. Our findings provide a basis for subsequent in vitro experiments, having important implications for the development of effective anti-COVID-19 drugs. MDPI 2022-06-30 /pmc/articles/PMC9268035/ /pubmed/35807455 http://dx.doi.org/10.3390/molecules27134210 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wang, Shuo
Fang, Xuexun
Wang, Ye
In Silico Screening of Novel TMPRSS2 Inhibitors for Treatment of COVID-19
title In Silico Screening of Novel TMPRSS2 Inhibitors for Treatment of COVID-19
title_full In Silico Screening of Novel TMPRSS2 Inhibitors for Treatment of COVID-19
title_fullStr In Silico Screening of Novel TMPRSS2 Inhibitors for Treatment of COVID-19
title_full_unstemmed In Silico Screening of Novel TMPRSS2 Inhibitors for Treatment of COVID-19
title_short In Silico Screening of Novel TMPRSS2 Inhibitors for Treatment of COVID-19
title_sort in silico screening of novel tmprss2 inhibitors for treatment of covid-19
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268035/
https://www.ncbi.nlm.nih.gov/pubmed/35807455
http://dx.doi.org/10.3390/molecules27134210
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