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

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.

Integrated Computational Approaches for Inhibiting Sex Hormone-Binding Globulin in Male Infertility by Screening Potent Phytochemicals

“…When docked against two different conformations of the Mpro protein of SARS-CoV 2, including typical substrate binding sites and ligand-induced substrate-binding sites, dorsilurin E had binding energies of −9.51 kcal/mol and −11.31 kcal/mol, respectively [ 81 ]. One of the top two terpenoids, with high binding scores, that was isolated from African medicinal plants, isoiguesterin, had −9.5 Kcal/mol binding energies when it interacted with the ACE2 and TMPRSS2 proteins to block the SARS-CoV 2 host-cell entry [ 82 ]. Therefore, the chosen molecule has previously shown inhibitory effects against viral proteins, encouraging further analysis against other protein targets for inhibition.…”

Methodology-Centered Review of Molecular Modeling, Simulation, and Prediction of SARS-CoV-2

“… 563 Other MM/PB(GB)SA-based drug repurposing works considering two or more targets include studies in the literature. 564 − 580 …”

“…The repurposing potential of 34 bioactive terpenes and their derivatives to Mpro and PLpro was also predicted by docking and MM/PBSA calculations . Other MM/PB­(GB)­SA-based drug repurposing works considering two or more targets include studies in the literature. − …”

Modern drug discovery applications for the identification of novel candidates for COVID-19 infections

“…24-dimethylene cycloartenol (83) and Isoiguesterin (84) have been shown to aim at ACE2 receptor site and the virus interaction with the host. These molecules showed its capacity to get bound and inhibit communications of hotspot 31 residual groups [ 84 ]. The human ACE2 residues at different amino acid sites of lysine and tyrosine are critical for coronavirus S-protein binding.…”