  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.
