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

Abstract

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 SARS-CoV-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.

Drug repurposing to face Covid-19: Celastrol, a potential leading drug capable of inhibiting SARS-CoV-2 replication and induced inflammation

“…The anti-inflammatory activity of celastrol is associated with down-regulation of NF-kB pathway mediated by suppression of IKK activation (SETHI et al, 2006), probably due to the formation of Michael’s adduct between its quinone methide and Cys179 from IKK 80,84 . In silico studies have reported that other quinone derivatives exhibit antiviral properties associated with the ability to form Michael’s adduct 85 , such as the glucocorticoids methylprednisolone and dexamethasone used to treat severe Covid-19 patients 86,87 .…”

Current Updates on Naturally Occurring Compounds Recognizing SARS-CoV-2 Druggable Targets

“…The covalent bond between the quinone carbonyl and the thiolate of Cys145 was hypothesized. To help this reaction mechanism, His41 captured the hydrogen atom from Cys145 that became prone to release a proton to the carbonyl quinone engaged with the thiolate [146]. preceded by curcumin [143,144].…”

“…To help this reaction mechanism, His41 captured the hydrogen atom from Cys145 that became prone to release a proton to the carbonyl quinone engaged with the thiolate [146]. By computational methods was observed that emodin (Figure 18b) binds Asp67, Ala71, and Lys74 residues of ACE2 receptor, and Asn448, Ala464, Val472, and Gly474 residues of Spike protein [147].…”

Recent efforts for drug identification from phytochemicals against SARS-CoV-2: Exploration of the chemical space to identify druggable leads

“… Group [Ref] Target Database/natural compounds (n) Methodology Outcome (best in silico leads) Ghosh et al ., ( Ghosh et al, 2021 ) M pro 113 Compounds of natural origin inhibiting M pro in SARS-CoV were retrieved, and 88 compounds were further considered for current work on the basis of available IC 50 and binding affinity data QSAR based data mining followed by structural and physiochemical interpretation (SPCI) analysis Rutin, Hespiridine, 22-Hydroxyhopan-3-one, Oolonghomobisflavan-A, Theasinensin-D, Quercetin, 3-vicianoside, Deacetylcentapicrin, Kouitchenside, Neohesperidin, Lignan, Myricitrin, Baicalin, Cyanidin 3-glucoside Cheke et al ., ( Cheke et al, 2020 ) Spike glycoproteins and ACE2 12 Natural compounds with reported antiviral attributes Molecular docking Indigo blue, glycyrrhizin, β-sitosterol, indirubin, bicylogermacrene, curcumin, hesperetin, rhein, and berberine Sahin et al ., ( Sahin et al, 2021 ) M pro Didemnins A, B and C Molecular docking Didemnin B Monajjemi et al ., ( Monajjemi et al, 2020 ) Protease Vidarabine, Cytarabine, Gemcitabine, and Matrine extracted from Gillan's leaves plants. Docking simulation and NMR investigation Cytarabine Saeed et al ., ( Saeed et al, 2020 ) Endoribonuclease NSP15 1624 Natural compounds (NuBBE database) Virtual screening and molecular docking, followed by molecular dynamics for top leads NuBBE-1970 and NuBBE-242 Caruso et al ., ( Caruso et al, 2020 ) M pro Quinone derivatives Molecular docking and DFT Embelin Basu et al ., ( Basu et al, 2020 ...…”