Alkaloids and flavonoids from African phytochemicals as potential inhibitors of SARS-Cov-2 RNA-dependent RNA polymerase: an in silico perspective

Abstract

Corona Virus Disease 2019 (COVID-19) is a pandemic caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Exploiting the potentials of phytocompounds is an integral component of the international response to this pandemic. In this study, a virtual screening through molecular docking analysis was used to screen a total of 226 bioactive compounds from African herbs and medicinal plants for direct interactions with SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). From these, 36 phytocompounds with binding affinities higher than the approved reference drugs (remdesivir and sobosivir), were further docked targeting the active sites of SARS-CoV-2, as well as SARS-CoV and HCV RdRp. A hit list of 7 compounds alongside two positive controls (remdesivir and sofosbuvir) and two negative controls (cinnamaldehyde and Thymoquinone) were further docked into the active site of 8 different conformations of SARS-CoV-2 RdRp gotten from molecular dynamics simulation (MDS) system equilibration. The top docked compounds were further subjected to predictive druglikeness and ADME/tox filtering analyses. Drugable alkaloids (10’–hydroxyusambarensine, cryptospirolepine, strychnopentamine) and flavonoids (usararotenoid A, and 12α-epi-millettosin), were reported to exhibit strong affinity binding and interactions with key amino acid residues in the catalytic site, the divalent-cation–binding site, and the NTP entry channel in the active region of the RdRp enzyme as the positive controls. These phytochemicals, in addition to other promising antivirals such as remdesivir and sofosbuvir, may be exploited towards the development of a cocktail of anti-coronavirus treatments in COVID-19. Experimental studies are recommended to validate these study.

Introduction

The Coronavirus Disease 2019 (COVID-19) is a pandemic caused by the outbreak of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and has resulted in increasing mortality and socio-economic burden. It is associated with high fever, cough, severe shortness of breathing, nausea, vomiting, and diarrhea in human populations; and has caused + 10 M infections with more than 0.5 M deaths worldwide.1,2 The pathogen, which is a new member of the betacoronavirus genus, is a positive-sense and single-stranded RNA virus similar to SARS-CoV and MERS-CoV (the Middle East Respiratory Syndrome coronavirus).3 Along with structural proteins (like spike glycoprotein and accessory proteins), these viral genomes encode non-structural proteins, including 3-chymotrypsin-like protease, papain-like protease, helicase and RNA-dependent RNA polymerase (RdRp).4
At present, no preventive vaccines or established antiviral therapies are available against COVID-19.5However, several repurposed drugs such as remdesivir, hydroxychloroquine, and chloroquine phosphate have shown promising results.6,7 Virtual screening, which is associated with search space minimization, economic feasibility, and high versatility, may be particularly valuable for rapidly finding a potent inhibitor of the COVID-19 virus. In the search for anti-coronavirus agents, important druggable targets include 3-chymotrypsin-like protease (3CLpro), papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp), and spike (S) proteins.8 The RdRp, a multi-domain protein, is a central component of coronaviral replication/transcription machinery that is able to catalyze RNA-template dependent formation of phosphodiester bonds between ribonucleotides in the presence of divalent metal ion.911 The polymerase domain is highly conserved and shares common structural features among coronaviruses, Hepatitis C Virus and other positive sense RNA viruses.1214 Thus, the viral RdRp or its catalyzed polymerization process has been explored as targets for developing several anti-viral drugs for treating Hepatitis C, Zika and coronaviruses.13,1517
Exploiting the potentials of phytomedicine, which is perhaps the oldest, and most assorted of all therapeutic systems, is an integral component of the international response to the COVID-19 pandemic, as highlighted by the WHO-China Joint Mission on COVID-19. Phytomedicine has efficacy against COVID-19 as many antiviral plants native to China have shown promising therapeutic potential against SARS-CoV and SARS-CoV-2 16,18,19 African herbs and medicinal plants provide a vibrant resource for chemopreventive phytochemicals as they could accumulate secondary metabolites more than plants from the northern hemisphere.20,21African plants and phytochemicals with documented antiviral, antimicrobial, antimalarial, antifungal exploited towards the development of prophylactic and therapeutic agents against the COVID-19.2225 This study focused on virtual screening of phytochemicals derived from African herbs and medicinal plants against the COVID-19 and related virus RNA-dependent RNA polymerase.

Publication Details

Authors / Researchers

Oludare M Ogunyemi, Gideon A Gyebi, Abdo A Elfiky, Saheed O Afolabi, Olalekan B Ogunro, Adegbenro P Adegunloye, and Ibrahim M Ibrahim

Published Year

December 2020

Journal / Conference

Antiviral Chemistry and Chemotherapy Volume 28

DOI

https://doi.org/10.1177/2040206620984076

Share