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

Abstract

BackgroundTargeting 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. ResultsThe 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. ConclusionThe 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.

Highlights

Targeting viral cell entry proteins is an emerging therapeutic strategy for inhibiting the first stage of SARS-CoV-2 infection
Protein preparation The crystal structures of proteins for the docking studies were retrieved from the Protein Databank with their various PDB identification codes [1R42: angiotensin-converting enzyme 2 (ACE2) [58]; 2OQ5: type II transmembrane serine proteinases (TMPR Transmembrane protease serine 2 (SS2)) [26]; 6vw1: 2019-nCoV chimeric receptor-binding domain complexed with its receptor human ACE2 (ACE2-RBD) [49] and coronaviruses spike protein (6VSB: SARS-CoV-2) [67]; (5X5B: SARS-CoV) [72] and (5x5c: MERS-CoV) [72]
The result from the docking analysis of the reference inhibitors and bioactive terpenoids with the human ACE2, transmembrane protease serine 2 (TMPRSS2), and SARS-CoV-2 spike protein is shown in Table S1

Summary

Introduction

Targeting viral cell entry proteins is an emerging therapeutic strategy for inhibiting the first stage of SARS-CoV-2 infection. The overall sequence similarity between S-protein of SARS-COV-2 and SARSCoV is approximately ~ 76%, affinity between S-RBD of SARS-COV-2 and ACE2 is found to be approximately four fold higher when compared with SARS-CoV RBD [12, 64] This molecular interaction is responsible for regulating both the cross-species and higher human-tohuman transmissions of SARS-CoV-2 [63, 74]. These protein effectors of viral attachment, membrane fusion, and cell entry are known as emerging targets for development of entry inhibitors, antibodies, and vaccines [74]

Methods

Results

Discussion

Conclusion