Rational approaches to discover SARS-CoV-2/ACE2 interaction inhibitors: Pharmacophore-based virtual screening, molecular docking, molecular dynamics and binding free energy studies

Mohsen Yazdani; Ameneh Jafari; Soodeh Mahdian; Mohsen Namazi; Sajjad Gharaghani

doi:10.1016/j.molliq.2023.121345

Rational approaches to discover SARS-CoV-2/ACE2 interaction inhibitors: Pharmacophore-based virtual screening, molecular docking, molecular dynamics and binding free energy studies

J Mol Liq. 2023 Apr 1:375:121345. doi: 10.1016/j.molliq.2023.121345. Epub 2023 Feb 1.

Authors

Mohsen Yazdani¹, Ameneh Jafari^{2

3}, Soodeh Mahdian⁴, Mohsen Namazi⁵, Sajjad Gharaghani¹

Affiliations

¹ Laboratory of Bioinformatics and Drug Design, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
² ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, P.O. Box: 15179/64311, Tehran, Iran.
³ Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
⁴ Department of Cellular and Molecular Biology, Faculty of Biological Science, North Tehran Branch, Islamic Azad University, Tehran, Iran.
⁵ Department of Bioinformatics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.

Abstract

The lack of effective treatment remains a bottleneck in combating the current coronavirus family pandemic, particularly coronavirus 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The infection of host cells by SARS-CoV-2 is mediated by the binding of its receptor-binding domain (RBD) on the spike (S) glycoprotein to the host angiotensin-converting enzyme (ACE2) receptor. As all developed and available vaccines against COVID-19 do not provide long-term immunity, the creation of an effective drug for the treatment of COVID-19 is necessary and cannot be ignored. Therefore, the aim of this study is to present a computational screening method to identify potential inhibitor candidates with a high probability of blocking the binding of RBD to the ACE2 receptor. Pharmacophore mapping, molecular docking, molecular dynamics (MD) simulations, and binding free-energy analyses were performed to identify potential inhibitor candidates against ACE2/SARS-CoV-2. In conclusion, we propose the compound PubChem-84280085 as a potential inhibitor of protein-protein interactions to disrupt the binding of the SARS-CoV-2-RBD to the ACE2 receptor.

Keywords: Drug design; Molecular docking; Molecular dynamics; Pharmacophore; Protein–protein interaction; SARS-CoV-2; Virtual screening.