Polyphenols as Potential Inhibitors of SARS-CoV-2 RNA Dependent RNA Polymerase (RdRp).

Yifei Wu,Carson Booth,Lauren Nicole Mullininx,Scott D Pegan,Kuan Y Chang,Lei Lou,Zhong-Ru Xie,David Crich,Madelyn C Hansen,Ellison Desrochers,Edward B Starling

doi:10.3390/molecules26247438

Abstract

An increasing number of studies have demonstrated the antiviral nature of polyphenols, and many polyphenols have been proposed to inhibit SARS-CoV or SARS-CoV-2. Our previous study revealed the inhibitory mechanisms of polyphenols against DNA polymerase α and HIV reverse transcriptase to show that polyphenols can block DNA elongation by competing with the incoming NTPs. Here we applied computational approaches to examine if some polyphenols can also inhibit RNA polymerase (RdRp) in SARS-CoV-2, and we identified some better candidates than remdesivir, the FDA-approved drug against RdRp, in terms of estimated binding affinities. The proposed compounds will be further examined to develop new treatments for COVID-19.

Highlights

Polyphenols, commonly found in plants, fruits, and tea, are antioxidants with many health benefits [1,2]
This study identifies three polyphenols with extremely low binding affinities to the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) as potential natural products for COVID-19 treatment
To develop effective inhibitors from polyphenols against SARS-CoV-2 RdRp, 480 polyphenols were docked onto SARS-CoV-2 RdRp (PDB ID: 7BV2)

Summary

Introduction

Polyphenols, commonly found in plants, fruits, and tea, are antioxidants with many health benefits [1,2]. Though not better than remdesivir, gallic acid had a large binding energy when docked to RdRp in a study of plant polyphenols by Nourhan et al, showing strong inhibitory potential [28]. After entry into a cell, ORF 1a and 1b are translated into two polyproteins that are further broken down into 16 non-structural proteins (nsps) [33] These proteins assemble to form a replication complex that transcribes and replicates the virus’ RNA [35]. To find potential therapeutic agents against COVID-19, this study screened 480 polyphenols to bind to SARS-CoV-2 RdRp. The structures of the 480 polyphenols were obtained from the Phenol-Explorer 3.6 database [40,41,42], and molecular docking was conducted using Maestro. This study identifies three polyphenols with extremely low binding affinities to the SARS-CoV-2 RdRp as potential natural products for COVID-19 treatment

Docking Analysis of Polyphenols against SARS-CoV-2 RdRp

Physicochemical Properties Prediction

Discussion

Ligand Preparation

Conclusions