Comprehensive virtual screening of 4.8 k flavonoids reveals novel insights into allosteric inhibition of SARS-CoV-2 MPRO

Abstract SARS-CoV-2 main protease is a common target for inhibition assays due to its high conservation among coronaviruses. Since flavonoids show antiviral activity, several in silico works have proposed them as potential SARS-CoV-2 main protease inhibitors. Nonetheless, there is reason to doubt ce...

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Autores principales:	Gabriel Jiménez-Avalos, A. Paula Vargas-Ruiz, Nicolás E. Delgado-Pease, Gustavo E. Olivos-Ramirez, Patricia Sheen, Manolo Fernández-Díaz, Miguel Quiliano, Mirko Zimic, COVID-19 Working Group in Perú
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/70a95756c88d494c934f01fa64c2c631
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spelling	oai:doaj.org-article:70a95756c88d494c934f01fa64c2c6312021-12-02T16:31:47ZComprehensive virtual screening of 4.8 k flavonoids reveals novel insights into allosteric inhibition of SARS-CoV-2 MPRO10.1038/s41598-021-94951-62045-2322https://doaj.org/article/70a95756c88d494c934f01fa64c2c6312021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-94951-6https://doaj.org/toc/2045-2322Abstract SARS-CoV-2 main protease is a common target for inhibition assays due to its high conservation among coronaviruses. Since flavonoids show antiviral activity, several in silico works have proposed them as potential SARS-CoV-2 main protease inhibitors. Nonetheless, there is reason to doubt certain results given the lack of consideration for flavonoid promiscuity or main protease plasticity, usage of short library sizes, absence of control molecules and/or the limitation of the methodology to a single target site. Here, we report a virtual screening study where dorsilurin E, euchrenone a11, sanggenol O and CHEMBL2171598 are proposed to inhibit main protease through different pathways. Remarkably, novel structural mechanisms were observed after sanggenol O and CHEMBL2171598 bound to experimentally proven allosteric sites. The former drastically affected the active site, while the latter triggered a hinge movement which has been previously reported for an inactive SARS-CoV main protease mutant. The use of a curated database of 4.8 k flavonoids, combining two well-known docking software (AutoDock Vina and AutoDock4.2), molecular dynamics and MMPBSA, guaranteed an adequate analysis and robust interpretation. These criteria can be considered for future screening campaigns against SARS-CoV-2 main protease.Gabriel Jiménez-AvalosA. Paula Vargas-RuizNicolás E. Delgado-PeaseGustavo E. Olivos-RamirezPatricia SheenManolo Fernández-DíazMiguel QuilianoMirko ZimicCOVID-19 Working Group in PerúNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-19 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Gabriel Jiménez-Avalos A. Paula Vargas-Ruiz Nicolás E. Delgado-Pease Gustavo E. Olivos-Ramirez Patricia Sheen Manolo Fernández-Díaz Miguel Quiliano Mirko Zimic COVID-19 Working Group in Perú Comprehensive virtual screening of 4.8 k flavonoids reveals novel insights into allosteric inhibition of SARS-CoV-2 MPRO
description	Abstract SARS-CoV-2 main protease is a common target for inhibition assays due to its high conservation among coronaviruses. Since flavonoids show antiviral activity, several in silico works have proposed them as potential SARS-CoV-2 main protease inhibitors. Nonetheless, there is reason to doubt certain results given the lack of consideration for flavonoid promiscuity or main protease plasticity, usage of short library sizes, absence of control molecules and/or the limitation of the methodology to a single target site. Here, we report a virtual screening study where dorsilurin E, euchrenone a11, sanggenol O and CHEMBL2171598 are proposed to inhibit main protease through different pathways. Remarkably, novel structural mechanisms were observed after sanggenol O and CHEMBL2171598 bound to experimentally proven allosteric sites. The former drastically affected the active site, while the latter triggered a hinge movement which has been previously reported for an inactive SARS-CoV main protease mutant. The use of a curated database of 4.8 k flavonoids, combining two well-known docking software (AutoDock Vina and AutoDock4.2), molecular dynamics and MMPBSA, guaranteed an adequate analysis and robust interpretation. These criteria can be considered for future screening campaigns against SARS-CoV-2 main protease.
format	article
author	Gabriel Jiménez-Avalos A. Paula Vargas-Ruiz Nicolás E. Delgado-Pease Gustavo E. Olivos-Ramirez Patricia Sheen Manolo Fernández-Díaz Miguel Quiliano Mirko Zimic COVID-19 Working Group in Perú
author_facet	Gabriel Jiménez-Avalos A. Paula Vargas-Ruiz Nicolás E. Delgado-Pease Gustavo E. Olivos-Ramirez Patricia Sheen Manolo Fernández-Díaz Miguel Quiliano Mirko Zimic COVID-19 Working Group in Perú
author_sort	Gabriel Jiménez-Avalos
title	Comprehensive virtual screening of 4.8 k flavonoids reveals novel insights into allosteric inhibition of SARS-CoV-2 MPRO
title_short	Comprehensive virtual screening of 4.8 k flavonoids reveals novel insights into allosteric inhibition of SARS-CoV-2 MPRO
title_full	Comprehensive virtual screening of 4.8 k flavonoids reveals novel insights into allosteric inhibition of SARS-CoV-2 MPRO
title_fullStr	Comprehensive virtual screening of 4.8 k flavonoids reveals novel insights into allosteric inhibition of SARS-CoV-2 MPRO
title_full_unstemmed	Comprehensive virtual screening of 4.8 k flavonoids reveals novel insights into allosteric inhibition of SARS-CoV-2 MPRO
title_sort	comprehensive virtual screening of 4.8 k flavonoids reveals novel insights into allosteric inhibition of sars-cov-2 mpro
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/70a95756c88d494c934f01fa64c2c631
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Comprehensive virtual screening of 4.8 k flavonoids reveals novel insights into allosteric inhibition of SARS-CoV-2 MPRO

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