Abstract
As an extension of our research against COVID-19, a multiphase
in silico
approach was applied in the selection of the three most common inhibitors (Glycyrrhizoflavone (
76
), Arctigenin (
94
)
,
and Thiangazole (
298
)) against papain-like protease, PLpro (PDB ID: 4OW0), among 310 metabolites of natural origin. All compounds of the exam set were reported as antivirals. The structural similarity between the examined compound set and
S88
, the co-crystallized ligand of PLpro, was examined through structural similarity and fingerprint studies. The two experiments pointed to Brevicollin (
28
), Cryptopleurine (
41
), Columbamine (
46
), Palmatine (
47
), Glycyrrhizoflavone (
76
), Licochalcone A (
87
), Arctigenin (
94
), Termilignan (
98
), Anolignan B (
99
), 4,5-dihydroxy-6″-deoxybromotopsentin (
192
), Dercitin (
193
), Tryptanthrin (
200
), 6-Cyano-5-methoxy-12-methylindolo [2, 3A] carbazole (
211
), Thiangazole (
298
), and Phenoxan (
300
). The binding ability against PLpro was screened through molecular docking, disclosing the favorable binding modes of six metabolites. ADMET studies expected molecules
28
,
76
,
94
,
200
, and
298
as the most favorable metabolites. Then, molecules
76
,
94
, and
298
were chosen through
in silico
toxicity studies. Finally, DFT studies were carried out on glycyrrhizoflavone (
76
) and indicated a high level of similarity in the molecular orbital analysis. The obtained data can be used in further
in vitro
and
in vivo
studies to examine and confirm the inhibitory effect of the filtered metabolites against PLpro and SARS-CoV-2.