Target-Based Virtual Screening and LC/MS-Guided Isolation Procedure for Identifying Phloroglucinol-Terpenoid Inhibitors of SARS-CoV-2.
Hou B, Zhang YM, Liao HY, Fu LF, Li DD, Zhao X, Qi JX, Yang W, Xiao GF, Yang L, Zuo ZY, Wang L, Zhang XL, Bai F, Yang L, Gao GF, Song H, Hu JM, Shang WJ, Zhou J.
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 <b>1</b>-<b>4</b> with inhibitory effects on SARS-CoV-2 in Vero E6 cells from the plant <i>Dryopteris wallichiana</i>. 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 <b>3</b> and <b>4</b> mainly inhibited SARS-CoV-2 3CLpro, with effective <i>K</i><sub>d</sub> values. Through docking and molecular dynamics modeling, the binding site is described, providing a comprehensive understanding of 3CLpro and interactions for <b>3</b>, including hydrogen bonds, hydrophobic bonds, and the spatial occupation of the B ring. Compounds <b>3</b> and <b>4</b> 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.