Computational studies reveal mechanism by which quinone derivatives can inhibit SARS-CoV-2. Study of embelin and two therapeutic compounds of interest, methyl prednisolone and dexamethasone
Autor
Caruso, Francesco
Rossi, Miriam
Pedersen, Jens Z.
Incerpi, Sandra
Institución
Resumen
Background: Quinones are reactive to proteins containing cysteine residues and the main protease
in Covid-19 contains an active site that includes Cys145. Embelin, a quinone natural product, is
known to have antiviral activity against influenza and hepatitis B. Preliminary studies by our
group also indicate its ability to inhibit HSV-1 in cultured cells. Methods: Docking and DFT
methods applied to the protease target. Results: a mechanism for this inhibition of the SARSCoV-2 Mpro protease is described, specifically due to formation of a covalent bond between
S(Cys145) and an embelin C(carbonyl). This is assisted by two protein amino acids (1)
N(imidazole-His41) which is able to capture H[S(Cys145)] and (2) HN(Met165), which donates a
proton to embelin O(carbonyl) forming an OH moiety that results in inhibition of the viral protease. A similar process is also seen with the anti-inflammatory drugs methyl prednisolone and
dexamethasone, used for Covid-19 patients. Methyl prednisolone and dexamethasone are methide
quinones, and possess only one carbonyl moiety, instead of two for embelin. Additional
consideration was given to another natural product, emodin, recently patented against Covid-19,
as well as some therapeutic quinones, vitamin K, suspected to be involved in Covid-19 action, and
coenzyme Q10. All show structural similarities with embelin, dexamethasone and methyl
prednisolone results. Conclusions: Our data on embelin and related quinones indicate that these
natural compounds may represent a feasible, strategic tool against Covid-19.