Structural stability of SARS-CoV-2 3CLpro and identification of quercetin as an inhibitor by experimental screening

Abstract

The global health emergency generated by coronavirus disease 2019 (COVID-19) has prompted the search for preventive and therapeutic treatments for its pathogen, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There are many potential targets for drug discovery and development to tackle this disease. One of these targets is the main protease, Mpro or 3CLpro, which is highly conserved among coronaviruses. 3CLpro is an essential player in the viral replication cycle, processing the large viral polyproteins and rendering the individual proteins functional. We report a biophysical characterization of the structural stability and the catalytic activity of 3CLpro from SARS-CoV-2, from which a suitable experimental in vitro molecular screening procedure has been designed. By screening of a small chemical library consisting of about 150 compounds, the natural product quercetin was identified as reasonably potent inhibitor of SARS-CoV-2 3CLpro (K i ~ 7 μM). Quercetin could be shown to interact with 3CLpro using biophysical techniques and bind to the active site in molecular simulations. Quercetin, with well-known pharmacokinetic and ADMET properties, can be considered as a good candidate for further optimization and development, or repositioned for COVID-19 therapeutic treatment.

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“…The 3C-like protease has an important role in SARS-CoV-2 and was so identified as a possible target for antiviral therapies. Quercetin-3-beta-galactoside was identified as a natural inhibitor of the protease by molecular docking [ 43 , 44 ]. The benefits of quercetin might be also modulated by zinc actions; the ionophore actions of quercetin increase the levels of zinc [ 45 ].…”

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“…SARS-CoV-2 M pro generates 12 non-structural proteins (Nsp4 and Nsp16) through the cleaves of the viral polyproteins, including RNA-dependent RNA polymerase (RdRp, Nsp12), and the helicase (Nsp13) [ 19 ]. Therefore, SARS-CoV-2 M pro is viewed as the best molecular target to block coronavirus replication [ [19] , [20] , [21] ]. Because comparable cleavage specificity has not been yet reported for human proteases, the inhibition of SARS-CoV-2 M pro is unlikely to cause any toxic effect to humans.…”

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“…Although the utilized dataset comprises activity toward SARS-CoV 3CLpro, exhibiting above 96% sequence identity to the SARS-CoV-2 3CLpro, in addition to the original dataset [ 25 ], we consider also a manually curated version of the same dataset, based on the following enrichment. We added to the dataset the following known SARS-CoV-2 3CLpro inhibitors 1 as active molecules, based on the already published results: ebselen, disulfiram, tideglusib, carmofur, shikonin, PX-12 [ 26 ], ritonavir [ 27 ], lopinavir, teicoplanin, oseltamivir, nitazoxanide, hydroxychloroquine, famciclovir, chloroquine, azithromycin, atazanavir, amoxicillin, aciclovir [ 28 ], and quercetin [ 29 ]. 2…”