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

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...

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Bibliographic Details
Published in:Journal of natural products (Washington, D.C.) D.C.), 2022-02, Vol.85 (2), p.327-336
Main Authors: Hou, Bo, Zhang, Yu-Min, Liao, Han-Yi, Fu, Li-Feng, Li, De-Dong, Zhao, Xin, Qi, Jian-Xun, Yang, Wei, Xiao, Geng-Fu, Yang, Lian, Zuo, Zheng-Yu, Wang, Lin, Zhang, Xiang-Lei, Bai, Fang, Yang, Liu, Gao, George F, Song, Hao, Hu, Jiang-Miao, Shang, Wei-Juan, Zhou, Jun
Format: Article
Language:English
Subjects:
Antiviral Agents - pharmacology
Biological Products - pharmacology
Chromatography, High Pressure Liquid
Chromatography, Liquid
Crystallography, X-Ray
Drug Delivery Systems
Dryopteris - chemistry
Magnetic Resonance Spectroscopy
Mass Spectrometry
Microbial Sensitivity Tests - methods
Molecular Docking Simulation
Molecular Structure
Phloroglucinol - pharmacology
SARS-CoV-2 - drug effects
Terpenes - pharmacology
Virtual Reality
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Summary: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.
ISSN:0163-3864
1520-6025
DOI:10.1021/acs.jnatprod.1c00805