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- Title
Interrelated Mechanism by Which the Methide Quinone Celastrol, Obtained from the Roots of Tripterygium wilfordii , Inhibits Main Protease 3CL pro of COVID-19 and Acts as Superoxide Radical Scavenger.
- Authors
Caruso, Francesco; Singh, Manrose; Belli, Stuart; Berinato, Molly; Rossi, Miriam
- Abstract
We describe the potential anti coronavirus disease 2019 (COVID-19) action of the methide quinone inhibitor, celastrol. The related methide quinone dexamethasone is, so far, among COVID-19 medications perhaps the most effective drug for patients with severe symptoms. We observe a parallel redox biology behavior between the antioxidant action of celastrol when scavenging the superoxide radical, and the adduct formation of celastrol with the main COVID-19 protease. The related molecular mechanism is envisioned using molecular mechanics and dynamics calculations. It proposes a covalent bond between the S(Cys145) amino acid thiolate and the celastrol A ring, assisted by proton transfers by His164 and His41 amino acids, and a π interaction from Met49 to the celastrol B ring. Specifically, celastrol possesses two moieties that are able to independently scavenge the superoxide radical: the carboxylic framework located at ring E, and the methide-quinone ring A. The latter captures the superoxide electron, releasing molecular oxygen, and is the feature of interest that correlates with the mechanism of COVID-19 inhibition. This unusual scavenging of the superoxide radical is described using density functional theory (DFT) methods, and is supported experimentally by cyclic voltammetry and X-ray diffraction.
- Subjects
COVID-19; QUINONE; SUPEROXIDES; DENSITY functional theory; CYCLIC voltammetry; DNA adducts
- Publication
International Journal of Molecular Sciences, 2020, Vol 21, Issue 23, p9266
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms21239266