Allosteric Modulation of Small Molecule Drugs on ACE2 Conformational Change upon Binding to SARS-CoV-2 Spike Protein

Duen Shian Wang, Hamed S. Hayatshahi, Vindi M. Jayasinghe-Arachchige, Jin Liu

Research output: Chapter in Book/Report/Conference proceedingConference contributionpeer-review

3 Scopus citations

Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused a worldwide pandemic (COVID-19). Drug repurposing studies, including drugs such as dexamethasone (DEX), chloroquine (CQ), and telmisartan (TLS), have been performed in COVID-19 clinical trials. DEX and CQ have been demonstrated in vitro to bind angiotensin-converting enzyme 2 (ACE2), a cellular entry receptor utilized by SARS-CoV-2. However, how DEX/CQ bind to ACE2 and their mechanisms of action are still unknown. We demonstrated that DEX, CQ, and TLS disrupt the interactions between SARS-CoV-2 spike protein and human ACE2 via binding to an allosteric site close to the viral spike protein binding region at the peptidase domain of ACE2, causing a conformational change of the ACE2. We defined four conformational states of ACE2 based on the two helices distances. Our molecular dynamics simulations suggested that binding to the viral spike protein shifted ACE2 conformation populations away from 'Open' conformation. Such conformation population shift is further enhanced by the Delta variant. The binding of the drugs to ACE2 rescues this conformation population shift allosterically to keep ACE2 in 'Open' conformation mostly. Our findings provide a potential insight that modulating the conformation of ACE2 may prevent SARS-CoV-2 invasion due to unfavored poses for spike protein binding.

Original languageEnglish
Title of host publicationProceedings - 2021 IEEE International Conference on Bioinformatics and Biomedicine, BIBM 2021
EditorsYufei Huang, Lukasz Kurgan, Feng Luo, Xiaohua Tony Hu, Yidong Chen, Edward Dougherty, Andrzej Kloczkowski, Yaohang Li
PublisherInstitute of Electrical and Electronics Engineers Inc.
Pages2587-2594
Number of pages8
ISBN (Electronic)9781665401265
DOIs
StatePublished - 2021
Event2021 IEEE International Conference on Bioinformatics and Biomedicine, BIBM 2021 - Virtual, Online, United States
Duration: 9 Dec 202112 Dec 2021

Publication series

NameProceedings - 2021 IEEE International Conference on Bioinformatics and Biomedicine, BIBM 2021

Conference

Conference2021 IEEE International Conference on Bioinformatics and Biomedicine, BIBM 2021
Country/TerritoryUnited States
CityVirtual, Online
Period9/12/2112/12/21

Keywords

  • ACE2 conformational change
  • Delta variant
  • SARS-CoV-2
  • allosteric
  • chloroquine
  • dexamethasone
  • telmisartan

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