Rutin and flavone analogs as prospective SARS-CoV-2 main protease inhibitors: In silico drug discovery study.

Mahmoud A A Ibrahim, Eslam A R Mohamed, Alaa H M Abdelrahman, Khaled S Allemailem, Mahmoud F Moustafa, Ahmed M Shawky, Ali Mahzari, Abdulrahim Refdan Hakami, Khlood A A Abdeljawaad, Mohamed A M Atia,

10.1016/j.jmgm.2021.107904

Research curated

Abstract

Coronavirus disease 2019 (COVID-19) is a new pandemic characterized by quick spreading and illness of the respiratory system. To date, there is no specific therapy for Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). Flavonoids, especially rutin, have attracted considerable interest as a prospective SARS-CoV-2 main protease (M^pro) inhibitor. In this study, a database containing 2017 flavone analogs was prepared and screened against SARS-CoV-2 M^pro using the molecular docking technique. According to the results, 371 flavone analogs exhibited good potency towards M^pro with docking scores less than -9.0 kcal/mol. Molecular dynamics (MD) simulations, followed by molecular mechanics-generalized Born surface area (MM/GBSA) binding energy calculations, were performed for the top potent analogs in complex with M^pro. Compared to rutin, PubChem-129-716-607 and PubChem-885-071-27 showed better binding affinities against SARS-CoV-2 M^pro over 150 ns MD course with ΔG_binding values of -69.0 and -68.1 kcal/mol, respectively. Structural and energetic analyses demonstrated high stability of the identified analogs inside the SARS-CoV-2 M^pro active site over 150 ns MD simulations. The oral bioavailabilities of probable SARS-CoV-2 M^pro inhibitors were underpinned using drug-likeness parameters. A comparison of the binding affinities demonstrated that the MM/GBSA binding energies of the identified flavone analogs were approximately three and two times less than those of lopinavir and baicalein, respectively. In conclusion, PubChem-129-716-607 and PubChem-885-071-27 are promising anti-COVID-19 drug candidates that warrant further clinical investigations.

Source: PubMed

Related molecules

Name	Synonyms	Genes
(2S,3S,4S,5R)-6-[5-[(2S,3S,4S,5R)-6-[2-(3,4-Dihydroxyphenyl)-5,7-dihydroxy-4-oxochromen-3-yl]oxy-3,4,5-trihydroxyoxane-2-carbonyl]oxy-7-hydroxy-2-(4-hydroxyphenyl)-4-oxochromen-3-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid
No no luteolin
3C-like protease	3CLpro, Mpro, SARS coronavirus main peptidase, 3CLpro-SARS-CoV-2	rep, ORF1a-1b

Related interactions

Target	Drug	Type	Result
3C-like protease	(2S,3S,4S,5R)-6-[5-[(2S,3S,4S,5R)-6-[2-(3,4-Dihydroxyphenyl)-5,7-dihydroxy-4-oxochromen-3-yl]oxy-3,4,5-trihydroxyoxane-2-carbonyl]oxy-7-hydroxy-2-(4-hydroxyphenyl)-4-oxochromen-3-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid	Computational	positive
3C-like protease	No no luteolin	Computational	positive