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While the COVID-19 pandemic continues to worsen, effective medicines that target the life cycle of SARS-CoV-2 are still under development. As more highly infective and dangerous variants of the coronavirus emerge, the protective power of vaccines will decrease or vanish. Thus, the development of drugs, which are free of drug resistance is direly needed. The aim of this study is to identify allosteric binding modulators from a large compound library to inhibit the binding between the Spike protein of the SARS-CoV-2 virus and human angiotensin-converting enzyme 2 (hACE2). The binding of the Spike protein to hACE2 is the first step of the infection of host cells by the coronavirus. We first built a compound library containing 77 448 antiviral compounds. Molecular docking was then conducted to preliminarily screen compounds which can potently bind to the Spike protein at two allosteric binding sites. Next, molecular dynamics simulations were performed to accurately calculate the binding affinity between the spike protein and an identified compound from docking screening and to investigate whether the compound can interfere with the binding between the Spike protein and hACE2. We successfully identified two possible drug binding sites on the Spike protein and discovered a series of antiviral compounds which can weaken the interaction between the Spike protein and hACE2 receptor through conformational changes of the key Spike residues at the Spike–hACE2 binding interface induced by the binding of the ligand at the allosteric binding site. We also applied our screening protocol to another compound library which consists of 3407 compounds for which the inhibitory activities of Spike/hACE2 binding were measured. Encouragingly, in vitro data supports that the identified compounds can inhibit the Spike–ACE2 binding. Thus, we developed a promising computational protocol to discover allosteric inhibitors of the binding of the Spike protein of SARS-CoV-2 to the hACE2 receptor, and several promising allosteric modulators were discovered.
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Allosteric regulation in SARS-CoV-2 spike protein
Allosteric regulation is common in protein–protein interactions and is thus promising in drug design. Previous experimental and simulation work supported the presence of allosteric regulation in the SARS-CoV-2 spike protein. Here the route of allosteric regulation in SARS-CoV-2 spike protein is examined by all-atom explicit solvent molecular dynamics simulations, contrastive machine learning, and the Ohm approach. It was found that peptide binding to the polybasic cleavage sites, especially the one at the first subunit of the trimeric spike protein, activates the fluctuation of the spike protein's backbone, which eventually propagates to the receptor-binding domain on the third subunit that binds to ACE2. Remarkably, the allosteric regulation routes starting from the polybasic cleavage sites share a high fraction (39–67%) of the critical amino acids with the routes starting from the nitrogen-terminal domains, suggesting the presence of an allosteric regulation network in the spike protein. Our study paves the way for the rational design of allosteric antibody inhibitors.
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- PAR ID:
- 10513600
- Publisher / Repository:
- Physical Chemistry, Chemical Physics
- Date Published:
- Journal Name:
- Physical Chemistry Chemical Physics
- Volume:
- 26
- Issue:
- 8
- ISSN:
- 1463-9076
- Page Range / eLocation ID:
- 6582-6589
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/D4CP00106K
