Effect of an Inhibitor on the ACE2-Receptor-Binding Domain of SARS-CoV‑2

• Published in: Journal of chemical information and modeling Vol. 62; no. 24; pp. 6574 - 6585
• Main Authors: Sharma, Gaurav, Song, Lin Frank, Merz, Kenneth M.
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 26.12.2022
• Subjects: Angiotensin-Converting Enzyme 2 - antagonists & inhibitors; Binding; Computational Biochemistry; Coronaviruses; COVID-19; Domains; Epithelium; Humans; Molecular dynamics; Molecular Dynamics Simulation; Protein Binding; Proteins; Receptors; SARS-CoV-2 - drug effects; Severe acute respiratory syndrome coronavirus 2; Viral diseases; China
• ISSN: 1549-9596; 1549-960X; 1549-960X
• DOI: 10.1021/acs.jcim.1c01283

The recent outbreak of COVID-19 infection started in Wuhan, China, and spread across China and beyond. Since the WHO declared COVID-19 a pandemic (March 11, 2020), three vaccines and only one antiviral drug (remdesivir) have been approved (Oct 22, 2020) by the FDA. The coronavirus enters human epithelial cells by the binding of the densely glycosylated fusion spike protein (S protein) to a receptor (angiotensin-converting enzyme 2, ACE2) on the host cell surface. Therefore, inhibiting the viral entry is a promising treatment pathway for preventing or ameliorating the effects of COVID-19 infection. In the current work, we have used all-atom molecular dynamics (MD) simulations to investigate the influence of the MLN-4760 inhibitor on the conformational properties of ACE2 and its interaction with the receptor-binding domain (RBD) of SARS-CoV-2. We have found that the presence of an inhibitor tends to completely/partially open the ACE2 receptor where the two subdomains (I and II) move away from each other, while the absence results in partial or complete closure. The current study increases our understanding of ACE inhibition by MLN-4760 and how it modulates the conformational properties of ACE2.