Antimalarial phytochemicals as potential inhibitors of SARS-CoV-2 guanine N7-methyltransferase (nsp 14): an integrated computational approach

Abstract

The inhibition of capping enzymes such as guanine-N7-methyltransferase (GMT) is an attractive target for regulating viral replication, transcription, virulence, and pathogenesis. Thus, compounds that target the Severe Acute Respiratory Syndrome Corona Virus 2 GMT (S2GMT) will enhance drug development against COVID-19. In this study, an in-house library of 249 phytochemicals from African medicinal plants was screened using computational approaches including homology modeling, molecular docking, molecular dynamic simulations, binding free energy calculations based on molecular mechanics/Poisson-Boltzmann surface area (MMPBSA) and Absorption-Distribution-Metabolism-Excretion-Toxicity (ADMET) analysis for inhibitors of S2GMT. The top-ten ranked phytochemicals (TTRP) obtained from the docking analysis to S2GMT were further docked to SARS-COV N7-MTase. Among the TTRP, the top-four ranked phytocompounds (TFRP) viz: 3 alkaloids (Isocryptolepine, 10’–Hydroxyusambarensine and Isostrychnopentamine) and a flavonoid (Mulberrofuran F) interacted strongly with critical catalytic residues whose interference either reduce or completely abolish N7-MTase activity, indicating their potential as capping machinery disruptors. The interactions of TFRP with the catalytic residues of S2GMT were preserved in a 100 ns simulated dynamic environment, thereby, demonstrating high degree of structural stability. The MMPBSA binding free energy calculations corroborated the docking scores with biscryptolepine having the highest binding free energy to S2GMT. The TFRP showed favourable drug-likeness and ADMET properties over a wide range of molecular descriptors. Therefore, the TFRP can be further explored as potential S2GMT inhibitors in in vitro and in vivo experiments.

Communicated by Ramaswamy H. Sarma

Keywords:

• SARS-COV-2
• molecular dynamic
• guanine-N7-methyltransferase
• phytochemicals
• antimalarials
• biscryptolepine

Acknowledgements

This research was supported by the computer resources and the technical support provided by Barcelona Supercomputing Center (BCV-2021-1-0010), Poznan Supercomputing Center, the e-infrastructure program of the Research Council of Norway via the supercomputer center of UiT–the Arctic University of Norway, and by the supercomputing infrastructure of the NLHPC (ECM-02), Powered@NLHPC. The authors are grateful to Taif University Researchers Supporting Project number (TURSP-2020/38), Taif University, Taif, Saudi Arabia and the members of the BioNet-AP: Bioinformatics Network on African Phytomedicine for COVID-19 research.

Disclosure statement

No potential conflict of interest was reported by the authors.

Authors contributions

Conceptualization, G.A.G.; visualization, G.A.G.; original draft draft preparation, G.A.G.; methodology, software, G.A.G ., O.M.O., J.F.L and A.J.B.; Writing - review & editing G.A.G., A.A.A., A.P.A., O.B.O. and S.O.A.; funding acquisition, H.P. A.B., S.S.A., and G.E.B; Supervision, H.P. All authors have read and agreed to the published version of the manuscript.

Availability of data and materials

The authors confirm that the data supporting the findings of this study are available within the article [and/or] its supplementary materials.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This work was partly funded by the Fundación Séneca de la Región de Murcia under Project 20988/PI/18 and the APC was funded by A.B., S.S.A., and G.E.B.