Unveiling the Mechanism of Action of a Novel Natural Dual Inhibitor of SARS-CoV-2 Mpro and PLpro with Molecular Dynamics Simulations

Overview

Journal Nat Prod Bioprospect

Publisher Springer

Specialty Biology

Date 2025 Jan 3

PMID 39753911

Authors

Xiaoxia Gu

Xiaotian Zhang

Xueke Zhang

Xinyu Wang

Weiguang Sun

Yonghui Zhang

Zhengxi Hu

Affiliations

Soon will be listed here.

Abstract

In the twenty-first century, we have witnessed multiple coronavirus pandemics. Despite declining SARS-CoV-2 cases, continued research remains vital. We report the discovery of sydowiol B, a natural product, as a dual inhibitor of SARS-CoV-2 main protease (Mpro) and papain-like protease (PLpro). Sydowiol B interacts with the nano-channel at the Mpro dimer interface and the PLpro active site. Molecular dynamics simulations suggest that sydowiol B inhibits Mpro by limiting active site expansion rather than inducing collapse. Furthermore, sydowiol B binding may amplify the fluctuation of two loops coordinating with the structural Zn in PLpro, displacing Zn from the zinc finger domain to the S2 helix. Sydowiol B and its analogue, violaceol I, exhibit broad-spectrum antiviral activity against homologous coronaviruses. Given the conservation of Mpro and PLpro, sydowiol B and violaceol I are promising leads for designing and developing anti-coronavirus therapies.

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