1.  Introduction
An outbreak of Coronavirus disease (COVID-19) has caused a pandemic situation across the globe. Although the outburst was first observed at Wuhan city in China, at present more than 200 countries and territories around the world have witnessed the COVID-19 fatalities affecting all age groups. As of July 03, 2020, more than 11 million people have been affected by the disease, with a fatality of 5,25,410 across the globe as per the WHO report. Unfortunately, there is no clinically approved drug or vaccine for COVID-19 as of now. The disease is caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), a member of the Coronaviridae family of viruses and it belongs to the same family Betacoronaviruses, like Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) (Chan et al., 2015; Elfiky & Azzam, 2020; Ibrahim et al., 2020). The symptoms of SARS-CoV-2 infection include fever, dry cough, shortness of breath, runny nose, and sore throat (Wu et al., 2020). SARS-CoV-2 is a positive-sense single-stranded RNA virus, and its genome is around 29.7 kB long with twelve putative open reading frames (ORFs) that encode different viral structural and non-structural proteins. There are four structural proteins in SARS-CoV-2, namely spike (S), envelope (E), membrane (M), and nucleocapsid (N), and all of them can potentially serve as an antigen for neutralizing antibody preparation as potential therapeutics (Boopathi et al., 2020).
Another potential drug target for SARS-CoV-2 is RNA‐dependent RNA polymerase (RdRp) (Figure 1), which is a key component of the replication machinery of the virus to make multiple copies of the RNA genome (Elfiky 2020c). RdRp in various coronaviruses are remarkably similar. For example, the RdRp of SARS-CoV exhibits ∼97% sequence similarity with that of SARS-CoV-2. More importantly, there is no human polymerase counterpart that resembles the sequence/structural homology with RdRp from coronaviruses, and hence, the development of RdRp inhibitors could be a potential therapeutic strategy without risk of crosstalk with human polymerases (Borgio et al., 2020; Subissi et al., 2014; Zhai et al., 2005). Very recently, Yin et al. reported the crystal structure RdRp of SARS-CoV-2 complexed with an antiviral drug, Remdesivir highlighting how the template-primer RNA is recognized by the polymerase enzyme and the chain elongation is inhibited by Remdesivir providing a basis for developing a wide range of effective inhibitors to overcome from SARS-CoV-2 infection (Yin et al., 2020). RdRp has been found to be an effective drug target for several other RNA viruses, spanning from the hepatitis C virus, zika virus to coronaviruses (Elfiky, 2017, 2019; Ganesan & Barakat, 2017). The active site of RdRp is highly conserved, and the catalytic domains contain two consecutive aspartate residues in a beta-turn joining β15 and β16 (Elfiky 2020c). The general structure of RdRp consists of 7 motifs (A to G) among them inner channel of catalytic sites represented by motif A to C, and they play a crucial role during the nucleotide addition cycle (Jia & Gong, 2019; Wu & Gong, 2018).
Figure 1.  The 3-dimensional crystal structure of RNA‐dependent RNA polymerase (RdRp). Epidemiological studies repetitively suggested that consumption of bioactive compounds (e.g. vitamins, phytochemicals, polyphenols, flavonoids, flavonols, and carotenoids etc.) has beneficial activity on human health and could minimize the risk of various diseases starting from cancers to different viral infections (Khan et al., 2020; Szajdek & Borowska, 2008). Traditional natural compounds have been consumed since ancient times as they exhibit less toxicity, low-cost availability, minimum side-effects and are rich in therapeutic resources. Some of the previous findings also suggest that naturally occurring compounds possess a wide range of antiviral properties against RNA viruses, including polio-virus type 1, parainfluenza virus type 3, and respiratory syncytial virus by inhibiting their replication (Lin et al., 2014). In that context, Ahmed-Belkacem et al. have screened more than forty potent natural flavonoids for their polymerase inhibition activity using HCV-NS5 strain and among the different flavonoids, quercetagetin showed strong HCV replication inhibitory activity in vitro (Ahmed-Belkacem et al., 2014). Previously, song et al. reported that green tea catechins, by disrupting the membrane of the influenza virus, inhibited neuraminidase in the crude system (Song et al., 2005). On a separate report, Takashi et al. reported that EGCG, a green tea polyphenol can inhibit the endonuclease activity of influenza A virus RNA polymerase. EGCG is also reported to interfere with viral replication via modulating the cellular redox environment (Ho et al., 2009; Kuzuhara et al., 2009). Therefore, the existing scientific evidence strongly suggests that natural flavonoids/polyphenol can act against SARS-CoV-2 (Aanouz et al., 2020; Elfiky 2020b; Elmezayen et al., 2020; Enmozhi et al., 2020). Because of the time-consuming process of new synthetic/semi-synthetic drug development, drug repurposing of phytomolecules is an ideal alternative in this urgent situation as the latter process is economical and scalable in a very short period of time (Adeoye et al., 2020; Islam et al., 2020; Muralidharan et al., 2020; Sinha et al., 2020). Hence, a comprehensive understanding of their binding to SARS-CoV-2 RdRp can yield interesting findings that can further be capitalized to develop COVID-19 drugs. Nevertheless, the apparent lack of cytotoxicity of polyphenols at even significantly high concentrations makes them potential antiviral drug candidates. In the present study, we selected a hundred natural polyphenols to assess their potential to act as SARS-CoV-2 RdRp inhibitors. The selected library was then explored to evaluate the binding affinity of individual polyphenols towards RdRp of the SARS-CoV-2 by molecular docking using AutoDock vina. Among the selected polyphenols, theaflavin (TF1), theaflavin-3′-O-gallate (TF2a), theaflavin-3′-gallate (TF2b), theaflavin 3,3′-digallate (TF3), hesperidin, EGCG, myricetin, and quercetagetin were found to be docked in the active site of RdRp of the SARS-CoV-2 with a highly favourable affinity for the binding pocket. Further to get a better understanding of the dynamics of the complexes, we performed a 150-nanoseconds molecular dynamic simulation with those eight polyphenols. The binding free energy components were calculated by the MM-PBSA. Remdesivir (Hendaus, 2020) and GTP (a physiological nucleotide) were taken as positive controls to validate our results.