SARS-CoV-2 host cell entry: an in silico investigation of potential inhibitory roles of terpenoids

Gideon A Gyebi; Oludare M Ogunyemi; Ibrahim M Ibrahim; Olalekan B Ogunro; Adegbenro P Adegunloye; Saheed O Afolabi

doi:10.1186/s43141-021-00209-z

SARS-CoV-2 host cell entry: an in silico investigation of potential inhibitory roles of terpenoids

J Genet Eng Biotechnol. 2021 Aug 5;19(1):113. doi: 10.1186/s43141-021-00209-z.

Authors

Gideon A Gyebi¹, Oludare M Ogunyemi², Ibrahim M Ibrahim³, Olalekan B Ogunro⁴, Adegbenro P Adegunloye⁵, Saheed O Afolabi⁶

Affiliations

¹ Department of Biochemistry, Faculty of Sciences and Technology, Bingham University, P.M.B 005, Karu, Nasarawa State, Nigeria. gyebi.gideon@binghamuni.edu.ng.
² Human Nutraceuticals and Bioinformatics Research Unit, Department of Biochemistry, Salem University, Lokoja, Nigeria.
³ Faculty of Sciences, Department of Biophysics Cairo University, Giza, Egypt.
⁴ Department of Biological Sciences, KolaDaisi University, Ibadan, Nigeria.
⁵ Department of Biochemistry, Faculty of Life Sciences, University of Ilorin, Ilorin, Nigeria.
⁶ Department of Pharmacology and Therapeutics, Faculty of Basic Medical Sciences, University of Ilorin, Ilorin, Nigeria.

Abstract

Background: Targeting viral cell entry proteins is an emerging therapeutic strategy for inhibiting the first stage of SARS-CoV-2 infection. In this study, 106 bioactive terpenoids from African medicinal plants were screened through molecular docking analysis against human angiotensin-converting enzyme 2 (hACE2), human transmembrane protease serine 2 (TMPRSS2), and the spike (S) proteins of SARS-CoV-2, SARS-CoV, and MERS-CoV. In silico absorption-distribution-metabolism-excretion-toxicity (ADMET) and drug-likeness prediction, molecular dynamics (MD) simulation, binding free energy calculations, and clustering analysis of MD simulation trajectories were performed on the top docked terpenoids to respective protein targets.

Results: The results revealed eight terpenoids with high binding tendencies to the catalytic residues of different targets. Two pentacyclic terpenoids (24-methylene cycloartenol and isoiguesteri) interacted with the hACE2 binding hotspots for the SARS-CoV-2 spike protein, while the abietane diterpenes were found accommodated within the S1-specificity pocket, interacting strongly with the active site residues TMPRSS2. 3-benzoylhosloppone and cucurbitacin interacted with the RBD and S2 subunit of SARS-CoV-2 spike protein respectively. These interactions were preserved in a simulated dynamic environment, thereby, demonstrating high structural stability. The MM-GBSA binding free energy calculations corroborated the docking interactions. The top docked terpenoids showed favorable drug-likeness and ADMET properties over a wide range of molecular descriptors.

Conclusion: The identified terpenoids from this study provides core structure that can be exploited for further lead optimization to design drugs against SARS-CoV-2 cell-mediated entry proteins. They are therefore recommended for further in vitro and in vivo studies towards developing entry inhibitors against the ongoing COVID-19 pandemic.

Keywords: ACE2; Abietane diterpenes: Molecular docking; SARS-CoV-2; Spike protein; TMPRSS2; Terpenoids.