Abstract
Flavonoids are phenolic compounds naturally found in plants and commonly consumed in diets. Herein, flavonoids were sequentially evaluated by a comparative in silico study associated with systematic literature search. This was followed by an in vitro study and enzyme inhibition assays against vital SARS-CoV-2 proteins including spike (S) protein, main protease (M pro ), RNA-dependent RNA-polymerase (RdRp), and human transmembrane serine protease (TMPRSS2). The results obtained revealed 10 flavonoids with potential antiviral activity. Out of them, silibinin showed promising selectivity index against SARS-CoV-2 in vitro. Screening against S protein discloses the highest inhibition activity of silibinin. Mapping the activity of silibinin indicated its excellent binding inhibition activity against SARS-CoV-2 S protein, M pro and RdRP at IC 50 0.029, 0.021, and 0.042 μM, respectively, while it showed no inhibition activity against TMPRSS2 at its IC 50(SARS-CoV-2) . Silibinin was tested safe on human mammalian cells at >7-fold its IC 50(SARS-CoV-2) . Additionally, silibinin exhibited >90% virucidal activity at 0.031 μM. Comparative molecular docking (MD) showed that silibinin possesses the highest binding affinity to S protein and RdRP at -7.78 and -7.15 kcal/mol, respectively. MDs showed that silibinin exhibited stable interaction with key amino acids of SARS-CoV-2 targets. Collectively, silibinin, an FDA-approved drug, can significantly interfere with SARS-CoV-2 entry and replication through multi-targeting activity.
Keywords: SARS-CoV-2; enzyme inhibition; flavonoids; in silico study; in vitro evaluation; silibinin.
【저자키워드】 SARS-CoV-2, flavonoids, Enzyme inhibition, in silico study, in vitro evaluation, silibinin., 【초록키워드】 TMPRSS2, S protein, molecular docking, flavonoids, protease, in vitro, antiviral activity, in silico, binding affinity, Screening, Replication, Protein, flavonoid, plants, virucidal, amino acids, RdRP, targets, plant, binding, SARS-CoV-2 S protein, Enzyme inhibition, Interaction, Safe, followed by, selectivity index, Comparative, Serine, FDA-approved drug, enzyme, key amino acids, SARS-CoV-2 entry, highest binding affinity, Compound, M pro, transmembrane serine protease, in vitro study, systematic literature search, mapping, SARS-CoV-2 protein, mammalian cell, inhibition activity, silibinin, inhibition assay, highest, significantly, indicated, evaluated, exhibited, interfere, key amino acid, was tested, 【제목키워드】 reveal,