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 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 Kd 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.