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Journal of hypertension · Aug 2021
The interaction of the severe acute respiratory syndrome coronavirus 2 spike protein with drug-inhibited angiotensin converting enzyme 2 studied by molecular dynamics simulation.
- Babak Nami, Avrin Ghanaeian, Kasra Ghanaeian, Rozhin Houri, Negin Nami, Armin Ghasemi-Dizgah, and Oana Caluseriu.
- Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada.
- J. Hypertens. 2021 Aug 1; 39 (8): 1705-1716.
BackgroundHypertension has been identified as the most common comorbidity in coronavirus disease 2019 (COVID-19) patients, and has been suggested as a risk factor for COVID-19 disease outcomes. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters host human cells via binding to host cell angiotensin-converting enzyme 2 (ACE2) receptors. Inhibition of ACE2 has been proposed as a potential therapeutic approach to block SARS-CoV-2 contagion. However, some experts suggest that ACE2 inhibition could worsen the infection. Here, we aimed to study the effect of ACE2 inhibition on the SARS-CoV-2 spike protein binding to ACE2.MethodCrystallographic structures of the SARS-CoV-2 spike protein, the spike receptor-binding domain, native ACE2, and the ACE2 complexed with MLN-4760 were used as the study model structures. The spike proteins were docked to the ACE2 structures and the dynamics of the complexes, ligand-protein, and protein-protein interactions were studied by molecular dynamics simulation for 100 ns.ResultsOur result showed that inhibition of ACE2 by MLN-4760 increased the affinity of the SARS-CoV-2 spike protein binding to ACE2. Results also revealed that spike protein binding to the ACE2 inhibited by MLN-4760 restored the enzymatic active conformation of the ACE2 from closed/inactive to open/active conformation by removing MLN-4760 binding from the ligand-binding pocket of ACE2.ConclusionWe conclude that using ACE2 inhibitors can increase the risk of SARS-CoV-2 infection and worsen COVID-19 disease outcome. We also found that the SARS-CoV-2 can abrogate the function of ACE2 inhibitors and rescue the enzymatic activity of ACE2. Therefore, ACE2 inhibition is not a useful treatment against COVID-19 infection.Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
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