Comparative evaluation of flavonoids reveals the superiority and promising inhibition activity of silibinin against SARS‐CoV‐2

Abstract

Flavonoids are phenolic compounds naturally found in plants and commonly consumed in diets. Herein, flavonoids were sequentially evaluated by a comparative in silico study associated with systematic literature search. This was followed by an in vitro study and enzyme inhibition assays against vital SARS‐CoV‐2 proteins including spike (S) protein, main protease (Mpro), RNA‐dependent RNA‐polymerase (RdRp), and human transmembrane serine protease (TMPRSS2). The results obtained revealed 10 flavonoids with potential antiviral activity. Out of them, silibinin showed promising selectivity index against SARS‐CoV‐2 in vitro. Screening against S protein discloses the highest inhibition activity of silibinin. Mapping the activity of silibinin indicated its excellent binding inhibition activity against SARS‐CoV‐2 S protein, Mpro and RdRP at IC50 0.029, 0.021, and 0.042 μM, respectively, while it showed no inhibition activity against TMPRSS2 at its IC50(SARS‐CoV‐2). Silibinin was tested safe on human mammalian cells at >7‐fold its IC50(SARS‐CoV‐2). Additionally, silibinin exhibited >90% virucidal activity at 0.031 μM. Comparative molecular docking (MD) showed that silibinin possesses the highest binding affinity to S protein and RdRP at −7.78 and −7.15 kcal/mol, respectively. MDs showed that silibinin exhibited stable interaction with key amino acids of SARS‐CoV‐2 targets. Collectively, silibinin, an FDA‐approved drug, can significantly interfere with SARS‐CoV‐2 entry and replication through multi‐targeting activity.

An update on inhibitors targeting RNA-dependent RNA polymerase for COVID-19 treatment: Promises and challenges

“…As we reviewed previously, some natural compounds and their derivatives have been repurposed as strong NNIs against SARS-CoV-2 RdRp. Besides, alkaloids [144] , [145] , plant polyphenols, including epigallocatechin-3-gallate (EGCG), silibinin, theaflavin [146] , [147] , [148] , [149] , and fungal derivative cordycepin [150] were also reported to establish strong and favorable binding interactions with the active site of SARS CoV-2 RdRp by molecular dynamic simulation. It is recommended to test these natural products in the laboratory to determine their inhibitory efficacy, as such compounds may be promising alternative and complementary therapies for COVID-19 due to their diverse range of biological and therapeutic properties.…”

Improved fluorescence‐based assay for rapid screening and evaluation of SARS‐CoV‐2 main protease inhibitors

“…Recently, a number of structurally disparate compounds have been identified as potent Mpro inhibitors, including ensitrelvir, baicalein, chloroquine, ebselen, echinatin, and silibinin, 26,[34][35][36][37][38] but a stringent validation is lacking. As such, we rigorously reevaluated the inhibition against Mpro by these compounds using combinational experiments, including FRET, FP, and ddRFP assays.…”

A Comprehensive Update of Various Attempts by Medicinal Chemists to Combat COVID-19 through Natural Products

“…It showed >90% inhibition of viral activity at a concentration of 0.031 µM. Moreover, in silico studies showed that this potent compound showed good binding affinity with both spike proteins and the main protease [59]. Elhusseiny et al (2022) analyzed the antiviral potential of aqueous extracts of Agaricus (A.)…”

“…Remdesivir was observed to be the most frequently used control group in many in vitro studies reported in the literature. Significant IC 50 and EC 50 values observed for remdesivir fell in the range of 0.086–13.1 μM [ 31 , 33 , 34 ] and 0.77–5 μM [ 35 , 43 , 47 , 59 ], respectively. Naturally occurring Compounds 16 (EC 50 = 1.69 μM [ 31 ]), 17 (IC 50 = 1.90 μM [ 47 ] and EC 50 = 3.35 μM [ 34 ]), 18 (IC 50 = 0.034 μM [ 35 ]), and 38 (IC 50 = 0.021 μM [ 59 ]) showed the most potent inhibitory activity.…”