3.1.  Molecular docking analysis

3.1.1.  The binding mode analysis and predicted binding affinity calculations of natural polyphenols against the SARS-CoV-2 RdRp
Herein, we investigated our natural polyphenol library against RdRp of the SARS-CoV-2 (PDB ID: 6M71) by molecular docking. The best conformation of the natural polyphenols was docked against the SARS-CoV-2 RdRp, and resulting binding energies are listed in Table 1.
Polyphenols exhibiting binding energy of −7.0 kcal/mol or lower (eight polyphenols) against RdRp of the SARS-CoV-2 are listed in Table 2 along with the ligand-amino acid interactions. Control compounds, GTP and remdesivir, exhibited the binding energy of −7.9 and −7.7 kcal/mol, respectively, against the SARS-CoV-2 RdRp. Eight polyphenols displayed significantly higher binding affinity among the selected hundred natural polyphenols docked against the SARS-CoV-2 RdRp, with binding energies of TF3, TF2b, TF1, TF2a, hesperidin, EGCG, myricetin and quercetagetin as −9.9, −9.6, −9.6, −9.3, −8.8, −7.3, −7.2 and −7.0 kcal/mol, respectively (highlighted in Table 1). Further, 2D LigPlot+ representation of RdRp and the above-mentioned eight polyphenols reveal the stable network of molecular interactions (see Table 2 and Figure S1 in the Supplementary Information).
Table 2.  Ligand-amino acid interactions of top eight scoring natural polyphenols against the SARS-CoV-2 RdRp.
S. No.  Compound name  Binding energy (kcal/mol)  No. of non-covalent interactions  Involved amino acids
1  TF3  −9.9  17  W617, K551, S549, D623, R836, S814, E811, F812, C813, D761, D618, S759, Y619, C622, R553, K621, D760
2  TF2b  −9.6  13  K551, Y619, D760, K798, W617, W800, D761, F812, C813, E811, D618, S549, A550
3  TF1  −9.6  12  W617, D761, D760, Y619, R553, K621, P620, F793, D164, S795, K798, D618
4  TF2a  −9.3  14  C813, F812, D761, D760, D618, K798, K551, A550, S549, K621, Y619, W800, W617, E811
5  Hesperidin  −8.8  13  Y619, D618, K798, S795, M794, P793, D164, V166, P620, K621, D623, R555, Y455
6  EGCG  −7.3  9  D623, Y619, K621, S795, C622, D618, M794, P620, K798
7  Myricetin  −7.2  10  W617, W800, D760, E811, K798, D618, Y619, C622, D761, F812
8  Quercetagetin  −7.0  8  R553, K545, K621, D623, C622, D760, P620, Y619
9  Remdesivir (Control)  −7.7  13  R553, K621, C622, D760, E811, W800, K798, P620, Y455, R624, Y619, D618, D761
10  GTP (Control)  −7.9  15  R624, T556, D623, D760, Y619, C622, K621, D452, A554, R553, Y455, R555, D761, D618, P620 In addition to remdesivir, here we observed that eight dietary polyphenols (TF1, TF2a, TF2b, TF3, hesperidin, EGCG, myricetin and quercetagetin) have significant potential to function as inhibitors of the SARS-CoV-2 RdRp. The top-eight scoring ligands for the SARS-CoV-2 RdRp (as highlighted in Table 1) suggest that these set of natural polyphenols can strongly bind to the catalytic site of the SARS-CoV-2 RdRp and are expected to inhibit the RdRp activity, and thus blocking the replication and preventing viral transcription. Many reports suggest polyphenols have low systemic toxicity, and they are highly beneficial for human health (Bhardwaj et al., 2020; Cory et al., 2018). TF1 and its gallate derivatives, collectively known as black tea polyphenols, previously have shown to exert antiviral activity against many viruses such as hepatitis virus and influenza A and B viruses (Chowdhury et al., 2018). Hesperidin is also known to possess antiviral activity by altering the immune system mainly via regulating interferons in the influenza A virus (Randall & Goodbourn, 2008). EGCG, a major green tea polyphenol, has several pharmacological properties, including antiviral activity (Carneiro et al., 2016; Moon & Morris, 2007). Similarly, myricetin has also been found to act as an inhibitor of the SARS coronavirus helicase (Yu et al., 2012). Quercetagetin also showed strong hepatitis C virus replication inhibitory activity in vitro (Ahmed-Belkacem et al., 2014). Thus, the set dietary polyphenols identified in the present study could be used as repurposed drugs for the treatment of the SARS-CoV-2 infection with further in-vitro and in-vivo validations.