Unveiling the mechanism of action of a novel natural dual inhibitor of SARS-CoV-2 Mpro and PLpro with molecular dynamics simulations

doi:10.1007/s13659-024-00486-4

Natural Products and Bioprospecting

2025, Vol. 15

Issue (1) : 3-3 DOI: 10.1007/s13659-024-00486-4

ORIGINAL ARTICLES

Unveiling the mechanism of action of a novel natural dual inhibitor of SARS-CoV-2 Mpro and PLpro with molecular dynamics simulations

Xiaoxia Gu, Xiaotian Zhang, Xueke Zhang, Xinyu Wang, Weiguang Sun, Yonghui Zhang, Zhengxi Hu

Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China

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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 Zn²⁺ in PLpro, displacing Zn²⁺ 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.

Keywords SARS-CoV-2 PLpro Mpro Natural product Dual inhibitor Nano-channel Antiviral agent

Fund:Thanks for the technical support by the Medical Subcenter of HUST Analytical & Testing Center. This research was financially supported by the National Program for Support of Top-notch Young Professionals (No. 0106514050), the National Natural Science Foundation of China (Nos. 82273811 and U22A20380), the Hubei Provincial Natural Science Foundation of China (No. 2024AFA028), the National Key Research and Development Program of China (No. 2021YFA0910500), the Major Science and Technology Project of Hubei Province (No. 2021ACA012), and TongjiRongcheng Center for Biomedicine, Huazhong University of Science and Technology.

Corresponding Authors: Weiguang SUN,E-mail:weiguang_sun@hust.edu.cn;Yonghui ZHANG,E-mail:zhangyh@mails.tjmu.edu.cn;Zhengxi HU,E-mail:hzx616@126.com E-mail: weiguang_sun@hust.edu.cn;zhangyh@mails.tjmu.edu.cn;hzx616@126.com

Issue Date: 15 February 2025

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Xiaoxia Gu,Xiaotian Zhang,Xueke Zhang, et al. Unveiling the mechanism of action of a novel natural dual inhibitor of SARS-CoV-2 Mpro and PLpro with molecular dynamics simulations[J]. Natural Products and Bioprospecting, 2025, 15(1): 3-3.

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http://npb.kib.ac.cn/EN/10.1007/s13659-024-00486-4 OR http://npb.kib.ac.cn/EN/Y2025/V15/I1/3

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