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

COVID-19 Working Group in Perú

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number15452
JournalScientific Reports
Volume11
Issue number1
DOIs
StatePublished - Dec 2021

Bibliographical note

Funding Information:
The authors extend their gratitude to Guido Choque and Eduardo Gushiken, for their conceptual contributions and feedback; to Fernando Antonio Zepeda Herrera, for his invaluable aid in the web scraping process; to Kate Gaskell, for her openness to improve the manuscript’s written expression; and specially to Alicia L. Arica-Sosa, for her help in absolving the reviewers’ comments related to docking. The authors are also thankful to Univer-sidad Privada San Juan Bautista for their economic support. This work was funded by the Consejo Nacional de Ciencia, Tecnología e Innovación Tecnológica (CONCYTEC, 048-2020) of Perú.

Publisher Copyright:
© 2021, The Author(s).

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