High-Throughput Virtual Screening of 4487 flavonoids: New insights on the structural inhibition of SARS-CoV-2 Main Protease

TL;DR

This study used high-throughput virtual screening of 4487 flavonoids to identify potential inhibitors of SARS-CoV-2 main protease, revealing promising candidates for COVID-19 therapeutic development.

Contribution

It introduces a comprehensive virtual screening approach targeting multiple sites of the SARS-CoV-2 main protease with a filtered flavonoid database, identifying novel potential inhibitors.

Findings

Identified top candidate flavonoids with strong binding energies to the protease sites.

Selected 15 promising compounds for further molecular dynamics validation.

Provided new insights into flavonoid interactions with SARS-CoV-2 main protease.

Abstract

COVID-19 presents a great threat to public health worldwide and the infectious agent SARS-CoV-2 is currently the target of much research aiming at inhibition. The virus' main protease is a dimeric enzyme that has only recently begun to be thoroughly described, opening the door for virtual screening more broadly. Here, a PAIN-filtered flavonoid database was screened against four sites of the protease: a free (normal) conformation of the Substrate Binding Site (NSBS), an induced-fit state of the SBS (ISBS), a Dimerization Site (DS) and a Cryptic Site (CS). The mean binding energies of the top five ligands from each site were -9.52, -11.512, -7.042 and -10.348 kcal/mol for the NSBS, the ISBS, the DS and the CS, respectively. For the DS and CS, these top five compounds were selected as candidates to bind their respective site. In the case of SBS, the top 30 ligands with the lowest binding energies from NSBS and ISBS were contrasted and the ones present in both lists were selected as the final candidates. The final list was: Dorsilurin E (FL3FQUNP0001), Euchrenone a11 (FL2FALNP0014), Kurziflavolactone C (FL2FA9NC0016), Licorice glycoside E (FL2F1AGSN001) and Taxifolin 3'- (6"-phenyl- acetylglucoside) (FL4DACGS0020) for the SBS; Sanggenol O (FL2FALNP0020), CHEMBL2171573, Kanzonol E (FL3F1ANP0001), CHEMBL2171584 and Abyssynoflavanone VI (FL2FACNP0014) for DS and CHEMBL2171598, CHEMBL2171577, Denticulaflavanol (FL5FAANR0001), Kurzichalcolactone (FL1CA9NC0001) and CHEMBL2171578 for CS. Virtual screening integrated several confirmation methods, including cross-docking assays and positive and negative controls. All 15 compounds are currently subjected to molecular dynamics so as to theoretically validate their binding to the protease.