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Screening approach by a combination of computational and in vitro experiments: identification of fluvastatin sodium as a potential SIRT2 inhibitor

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Abstract

Background

Sirtuins (SIRTs) are NAD+-dependent deacetylases that play various roles in numerous pathophysiological processes, holding promise as therapeutic targets worthy of further investigation. Among them, the SIRT2 subtype is closely associated with tumorigenesis and malignancies. Dysregulation of SIRT2 activation can regulate the expression levels of related genes in cancer cells, leading to tumor occurrence and metastasis.

Methods

In this study, we used computer simulations to screen for novel SIRT2 inhibitors from the FDA database, based on which 10 compounds with high docking scores and good interactions were selected for in vitro anti-pancreatic cancer metastasis testing and enzyme binding inhibition experiments. The results showed that fluvastatin sodium may possess inhibitory activity against SIRT2. Subsequently, fluvastatin sodium was subjected to molecular docking experiments with various SIRT isoforms, and the combined results from Western blotting experiments indicated its potential as a SIRT2 inhibitor. Next, molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations were performed, revealing the binding mode of fluvastatin sodium at the SIRT2 active site, further validating the stability and interaction of the ligand–protein complex under physiological conditions.

Results

Overall, this study provides a systematic virtual screening workflow for the discovery of SIRT2 activity inhibitors, identifies the potential inhibitory effect of fluvastatin sodium as a lead compound on SIRT2, and opens up a new direction for develo** highly active and selectively targeted SIRT2 inhibitors.

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Data availability

Available on request.

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Funding

The research was financially supported by the Natural Science Foundation of Liaoning Province (2022-MS-247), the Career Development Support Program for Young and Middle-aged Teachers at Shenyang Pharmaceutical University (ZQN2021001), the General Project of Liaoning Province Education Department (JYTMS20231359), and the National College Students Innovation and Entrepreneurship Training Program (202210163034).

Author information

Author notes

  1. ** Yang and Hanxun Wang contributed equally.

Authors and Affiliations

  1. Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenhe District, 103 Wenhua Road, Shenyang, 110016, People’s Republic of China

    ** Yang, Hanxun Wang & Chao Ma

  2. School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenhe District, 103 Wenhua Road, Shenyang, 110016, People’s Republic of China

    Jiale Liu & Chao Ma

  3. School of Life Sciences and Biopharmaceutical Science, Shenyang Pharmaceutical University, Shenhe District, 103 Wenhua Road, Shenyang, 110016, People’s Republic of China

    Enlong Ma, **nxin ** & Yanchun Li

Authors
  1. ** Yang
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Contributions

All authors contributed to the study conception and design. Study conception and design: ** Yang, Chao Ma. Acquisition of data: ** Yang, Hanxun Wang, Enlong Ma. Analysis and interpretation of data: ** Yang, Hanxun Wang, Jiale Liu. Drafting of the manuscript: ** Yang. Critical revision: Yanchun Li, **nxin **. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Yanchun Li or Chao Ma.

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Yang, J., Wang, H., Liu, J. et al. Screening approach by a combination of computational and in vitro experiments: identification of fluvastatin sodium as a potential SIRT2 inhibitor. J Mol Model 30, 188 (2024). https://doi.org/10.1007/s00894-024-05988-z

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