Target-Based Virtual Screening and LC/MS-Guided Isolation Procedure for Identifying Phloroglucinol-Terpenoid Inhibitors of SARS-CoV-2

Abstract

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to more than 5 million deaths worldwide to date. Due to the limited therapeutic options so far available, target-based virtual screening with LC/MS support was applied to identify the novel and high-content compounds 1 – 4 with inhibitory effects on SARS-CoV-2 in Vero E6 cells from the plant Dryopteris wallichiana . These compounds were also evaluated against SARS-CoV-2 in Calu-3 cells and showed unambiguous inhibitory activity. The inhibition assay of targets showed that compounds 3 and 4 mainly inhibited SARS-CoV-2 3CLpro, with effective K d values. Through docking and molecular dynamics modeling, the binding site is described, providing a comprehensive understanding of 3CLpro and interactions for 3 , including hydrogen bonds, hydrophobic bonds, and the spatial occupation of the B ring. Compounds 3 and 4 represent new, potential lead compounds for the development of anti-SARS-CoV-2 drugs. This study has led to the development of a target-based virtual screening method for exploring the potency of natural products and for identifying natural bioactive compounds for possible COVID-19 treatment.

Exploring new catechin derivatives as SARS-CoV-2 Mpro inhibitors from tea by molecular networking, surface plasma resonance, enzyme inhibition, induced fit docking, and metadynamics simulations

“…SPR is an efficient approach for drug discovery. Hou et al used SPR to evaluate the antiviral activity of novel phloroglucinol-terpenoid against SARS-CoV-2 M pro [ 8 ]. We assessed the direct binding affinities between the 12 catechin derivatives and M pro by analyzing their equilibrium dissociation constants (K D ).…”

“…Besides, non-peptidic inhibitors inactivate the M pro by forming covalent, hydrogen, and hydrophobic bonds. For example, phloroglucinol-terpenoids have vital interactions with SARS-CoV-2 M pro , including hydrogen bonds, hydrophobic bonds, and the spatial occupation of the B ring [ 8 ]; the pyrogallol moiety of myricetin covalently binds with the –SH group and modifies the catalytic cysteine as an electrophile warhead [ 9 ]; proanthocyanidins and pentagalloylglucose as natural polyphenols have potential antiviral activity [ 10 ].…”

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

“…Compound 30 was virtually screened on AutoDock 4 to see the binding interactions between the ligand and amino acid residues of 3CL pro . It was noted that Compound 30 formed H-bonds with MET165, ASN142, GLU166, and GLN192 and hydrophobic interactions with PHE140 [ 52 ]. Kim et al (2022) identified the antiviral potential of mulberrin (kuwanon C) 31 ( Figure 5 ), isolated from the commonly known mulberry plant.…”

Methylene-bridged dimeric natural products involving one-carbon unit in biosynthesis

“…Thus, these compounds represent new and potential lead compounds for the development of anti-SARS-CoV-2 drugs. 44 Chemical investigations on the plant Cannabis sativa (Cannabaceae) led to the isolation of cannabisol ( 64 ), the first example of methylene-bridged dimeric cannabinoid. 45 In 2020, cannabitwinol ( 65 ), the second member of methylene-bridged dimeric phytocannabinoids, was isolated from hemp ( Cannabis sativa L.) industrial extract.…”