Investigation on the potential inhibitory activity of Foeniculum vulgare Seed Extract towards recombinant SARS-CoV-2 3CLpro

Abstract

The CoronaVirus Disease 2019 (COVID-19) caused by SARS-CoV-2 continues to be a global pandemic with substantial socioeconomic damages. Exploration of bioactive compounds from herbal resources with potential anti SARS-CoV-2 effects are currently on the rise. In particular, naturally-derived flavonoids are reported for its capability to inhibit 3-chymotrypsin like-protease (3CL), a promising drug target that is essential for SARS-CoV-2 replication and formation. In this paper, the flavonoid compounds in Foeniculum vulgare semen (Fennel seed) ethanolic crude extract are identified using UPLC-ESI-MS/MS, followed by binding affinity prediction of the identified flavonoid compounds toward SARS-CoV-2 3CL procrystal structure through in silico approaches, before ultimately assessing the inhibition level of the extract towards recombinant SARS-CoV-2 3CLpro in vitro. The results indicated that F. vulgare seed extract contains the flavonol class of flavonoids, specifically quercetin, kaempferol, and its glycosylated moieties which are well documented by previous studies to exert SARS-CoV-2 3CLpro inhibitory effects. Molecular docking analysis revealed strong binding affinity values of <-7 kcal/mol for all identified flavonols, with glycosylated moieties displaying a more negative value than aglycone flavonols. Quercetin-3-O-rutinoside exhibited the highest binding affinity of -8.8 kcal/mol, and most flavonols have interactions with the Cys145 and Glu166 active site residues of SARS-CoV-2 3CLpro crystal structure (6LU7). F. vulgare seed extract is also revealed to successfully inhibit SARS-CoV-2 3CLpro with a half-maximum inhibitory concentration (IC) of 58.55 ± 7.29 ppm. Overall, the findings are able to provide important insights for further research andinnovation of novel anti SARS-CoV-2 drugs.