Plant-derived natural polyphenols as potential antiviral drugs against SARS-CoV-2viaRNA‐dependent RNA polymerase (RdRp) inhibition: anin-silicoanalysis

Abstract

The sudden outburst of Coronavirus disease (COVID-19) caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) poses a massive threat to global public health. Currently, no therapeutic drug or vaccine exists to treat COVID-19. Due to the time taking process of new drug development, drug repurposing might be the only viable solution to tackle COVID-19. RNA-dependent RNA polymerase (RdRp) catalyzes SARS-CoV-2 RNA replication and hence, is an obvious target for antiviral drug design. Interestingly, several plant-derived polyphenols effectively inhibit the RdRp of other RNA viruses. More importantly, polyphenols have been used as dietary supplementations for a long time and played beneficial roles in immune homeostasis. We were curious to study the binding of polyphenols with SARS-CoV-2 RdRp and assess their potential to treat COVID-19. Herein, we made a library of polyphenols that have shown substantial therapeutic effects against various diseases. They were successfully docked in the catalytic pocket of RdRp. The investigation reveals that EGCG, theaflavin (TF1), theaflavin-3'-O-gallate (TF2a), theaflavin-3'-gallate (TF2b), theaflavin 3,3'-digallate (TF3), hesperidin, quercetagetin, and myricetin strongly bind to the active site of RdRp. Further, a 150-ns molecular dynamic simulation revealed that EGCG, TF2a, TF2b, TF3 result in highly stable bound conformations with RdRp. The binding free energy components calculated by the MM-PBSA also confirm the stability of the complexes. We also performed a detailed analysis of ADME prediction, toxicity prediction, and target analysis for their druggability. Overall, our results suggest that EGCG, TF2a, TF2b, TF3 can inhibit RdRp and represent an effective therapy for COVID-19.

Insilico drug repurposing using FDA approved drugs against Membrane protein of SARS-CoV-2

“…The MM-PBSA method was used to estimate the binding affinity of ligands from the last 10 ns simulation trajectories (Table S1). Previous studies confirmed that binding free energy values lower than -30 kJ/mol can be considered for binding, however lower binding free energy values more favorable for interactions 63,64 65 . The binding affinity of the drug Remedesivir was also analyzed with SARS-CoV-RdRp ( Figure S3).…”

Therapeutic Potential of EGCG, a Green Tea Polyphenol, for Treatment of Coronavirus Diseases

“…Polyphenols, including EGCG, have shown inhibitory effects on the RdRp of the influenza A virus [ 48 ]. In silico structural analysis has suggested that EGCG interacts with SARS-CoV-2 RdRp and forms a stable complex, indicating that EGCG potentially interferes with SARS-CoV-2 RdRp function [ 49 ].…”

“…EGCG is an abundant tea polyphenol in brewed green tea, and many reports provide evidence that EGCG can efficiently block 3CL protease, an essential enzyme for coronavirus replication [ 6 , 39 ]. Moreover, additional coronavirus targets of EGCG such as RdRp and spike protein have been proposed [ 49 , 51 ]. Finally, EGCG treatment interferes with the replication of coronaviruses in cell culture systems [ 43 ].…”

Targeting Neurological Manifestations of Coronaviruses by Candidate Phytochemicals: A Mechanistic Approach

“…As previously mentioned, RdRp catalyzes SARS-CoV-2 RNA replication and thereby is considered an important target for antiviral drug design. Molecular docking investigation revealed that EGCG, theaflavin, theaflavin-3′-O-gallate, theaflavin-3′-gallate, theaflavin 3,3′-digallate, hesperidin, quercetagetin, and myricetin bind to the active site of RdRp (Singh et al, 2020). Overall, flavonoids and indole chalcones could combat SARS-CoV-2 (Vijayakumar et al, 2020).…”

“…Theaflavins, a group of polyphenols formed after the fermentation of green tea, have a very strong affinity to bind to RdRp (Lung et al, 2020;Singh et al, 2020). Lung and co-workers reported that theaflavin had a high affinity for RdRp of SARS-CoV2, SARS-CoV, and MERS-CoV (Lung et al, 2020).…”