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

Abstract

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.

All-Atom Simulations of Human ACE2-Spike Protein RBD Complexes for SARS-CoV-2 and Some of its Variants: Nature of Interactions and Free Energy Diagrams for Dissociation of the Protein Complexes

“…The binding of RBD with human ACE2 has been studied in many recent studies through computational means. − Although these studies have greatly contributed to our understanding of the RBD-ACE2 binding process, many details of the molecular mechanism of the binding, the process of unbinding and associated free energy diagrams, and their variations with mutation still remain open. For example, while the experimental work of ref reported that the receptor binding domains of SARS-CoV-2 and SARS-CoV-1 bind with ACE2 with similar affinities, the biomechanical force measurements and computational studies of refs and − reported that SARS-CoV-2 binds with ACE2 with higher affinity than SARS-CoV-1.…”

Molecular Imaging of ACE2 Expression in Infectious Disease and Cancer

“…The S1 domain is subdivided into the n-terminal domain, the RBD, and the c-terminal domain. In the "open" conformation, the receptor-binding site on the RBD is transiently exposed, allowing 17 amino acids on the binding site to interact with 20 amino acids on ACE2 [17][18][19]. RBD and ACE2 binding is similar between SARS-CoV and SARS-CoV-2.…”

ChatGPT in Drug Discovery

“…3 Drug discovery using computational chemistry is the application of computer-based methods to assist in the discovery of new medications. 5,7,8 It involves the use of computer simulations and modeling techniques to predict the properties and interactions of potential drug molecules. These methods can be used to understand the structure and behavior of proteins and other biological targets, and to design and optimize new compounds that can bind to these targets and modulate their activity.…”