Sirtuins (SIRT) 是 NAD 依赖性脱乙酰酶，在众多病理生理过程中发挥多种作用，有望成为值得进一步研究的治疗靶点。其中，SIRT2亚型与肿瘤发生和恶性肿瘤密切相关。 SIRT2激活失调可以调节癌细胞中相关基因的表达水平，导致肿瘤的发生和转移。在本研究中，我们利用计算机模拟从FDA数据库中筛选新型SIRT2抑制剂，在此基础上筛选出10种高对接化合物选择分数和良好相互作用进行体外抗胰腺癌转移测试和酶结合抑制实验。结果表明氟伐他汀钠可能对SIRT2具有抑制活性。随后，氟伐他汀钠与各种SIRT亚型进行分子对接实验，Western blotting实验的综合结果表明其作为SIRT2抑制剂的潜力。接下来，通过分子对接、分子动力学（MD）模拟和结合自由能计算，揭示了氟伐他汀钠在SIRT2活性位点的结合模式，进一步验证了配体-蛋白质复合物在生理条件下的稳定性和相互作用。该研究为SIRT2活性抑制剂的发现提供了系统的虚拟筛选工作流程，确定了氟伐他汀钠作为先导化合物对SIRT2的潜在抑制作用，为开发高活性、选择性靶向的SIRT2抑制剂开辟了新方向。© 2024作者获得 Springer-Verlag GmbH（德国施普林格自然公司的一部分）的独家许可。

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.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.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 developing highly active and selectively targeted SIRT2 inhibitors.© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.