Metabolites profiling and cheminformatics bioprospection of selected medicinal plants against the main protease and RNA-dependent RNA polymerase of SARS-CoV-2

Abstract

Despite the existence of some vaccines, SARS-CoV-2 (S-2) infections persist for various reasons relating to vaccine reluctance, rapid mutation rate, and an absence of specific treatments targeted to the infection. Due to their availability, low cost and low toxicity, research into potentially repurposing phytometabolites as therapeutic alternatives has gained attention. Therefore, this study explored the antiviral potential of metabolites of some medicinal plants [Spondias mombin, Macaranga barteri and Dicerocaryum eriocarpum (Sesame plant)] identified using liquid chromatography-mass spectrometry (LCMS) as possible inhibitory agents against the S-2 main protease (S-2 MP) and RNA-dependent RNA polymerase (RP) using computational approaches. Molecular docking was used to identify the compounds with the best affinities for the selected therapeutics targets. Afterwards, compounds with poor physicochemical characteristics, pharmacokinetics, and drug-likeness were screened out. The top-ranked compounds were further subjected to a 120-ns molecular dynamics (MD) simulation. Only quercetin 3-O-rhamnoside (−48.77 kcal/mol) had higher binding free energy than the reference standard (zafirlukast) (−44.99 kcal/mol) against S-2 MP. Conversely, all the top-ranked compounds (ellagic acid hexoside, spiraeoside, apigenin-4’-glucoside and chrysoeriol 7-glucuronide) except gnetin L (−24.24 kcal/mol) had higher binding free energy (−55.19 kcal/mol, −52.75 kcal/mol, −47.22 kcal/mol and −43.35 kcal/mol) respectively, against S-2 RP relative to the reference standard (−34.79 kcal/mol). The MD simulations study further revealed that the investigated inhibitors are thermodynamically stable and form structurally compatible complexes that impede the regular operation of the respective S-2 therapeutic targets. Although, these S-2 therapeutic candidates are promising, further in vitro and in vivo evaluation is required and highly recommended.

Communicated by Ramaswamy H. Sarma

Keywords:

• Main protease
• RNA-dependent RNA polymerase
• phytochemicals
• ADMET study
• molecular dynamics simulation

Acknowledgments

The DUT Doctoral Scholarship Scheme to A. A. Lanrewaju is duly acknowledged. The Centre for High-Performance Computing (CHPC), South Africa, is equally acknowledged for granting access to the computing systems used in this study.

Author’s contributions

Conceptualization, S.S., A.M.E. and A.A.L.; methodology, A.A.L.; software, S.S.; validation, A.A.L. and S.S; formal analysis, A.A.L.; investigation, A.A.L; resources, S.S.; data curation, A.A.L. and S.S.; writing—original draft preparation, A.A.L.; writing—review and editing, A.M.E., M.M.N, F.M.S, S.S; supervision, A.M.E., F.M.S and S.S.; funding acquisition, A.M.E., F.M.S. and S.S. All authors read and contributed to the critical review of the manuscript for intellectual content and approved the submission for publication.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

The data is contained within the article or supplementary material.

Supplementary description

Additional information on the LCMS profiling of the metabolites from the selected plants, docking scores for 77 plant metabolites against S-2 MP and RP and 2D interaction plots of top rank compounds against S-2 MP and RP after 120 ns simulation (Supplementary Tables S1–S3).

Additional information

Funding

This study was based on the financial assistance received from the Directorate of Research and Postgraduate Support, Durban University of Technology (DUT), and the South African Medical Research Council (SAMRC) under a Self-Initiated Research Grant as well as the National Research Foundation (NRF) Research Development Grant for Rated Researchers (Grant number 120433) and the Competitive Programme for Rated Researchers Support (SRUG2204193723) to S. Sabiu. We also acknowledge Water Research Commission (WRC) of South Africa for the grant (Project no. K5/C2020-2021-00181) awarded to am Enitan-Folami.