Discovery of naturally occurring inhibitors against SARS-CoV-2 3CL pro from Ginkgo biloba leaves via large-scale screening.

3-Chymotrypsin-like protease (3CL ^pro ) is a virally encoded main proteinase that is pivotal for the viral replication across a broad spectrum of coronaviruses. This study aims to discover the naturally occurring SARS-CoV-2 3CL ^pro inhibitors from herbal constituents, as well as to investigate the inhibitory mechanism of the newly identified efficacious SARS-CoV-2 3CL ^pro inhibitors. Following screening of the inhibitory potentials of eighty herbal products against SARS-CoV-2 3CL ^pro , Ginkgo biloba leaves extract (GBLE) was found with the most potent SARS-CoV-2 3CL ^pro inhibition activity (IC ₅₀  = 6.68 μg/mL). Inhibition assays demonstrated that the ginkgolic acids (GAs) and the bioflavones isolated from GBLE displayed relatively strong SARS-CoV-2 3CL ^pro inhibition activities (IC ₅₀  < 10 μM). Among all tested constituents, GA C15:0, GA C17:1 and sciadopitysin displayed potent 3CL ^pro inhibition activities, with IC ₅₀ values of less than 2 μM. Further inhibition kinetic studies and docking simulations clearly demonstrated that two GAs and sciadopitysin strongly inhibit SARS-CoV-2 3CL ^pro via a reversible and mixed inhibition manner. Collectively, this study found that both GBLE and the major constituents in this herbal product exhibit strong SARS-CoV-2 3CL ^pro inhibition activities, which offer several promising leading compounds for developing novel anti-COVID-19 medications via targeting on 3CL ^pro .
(Copyright © 2021. Published by Elsevier B.V.)