ABSTRACT The sirtuins are members of the histone deacetylase family of proteins that participate in a variety of cellular functions and play a close role in cancers. Exploring the proper inhibitors for SIRT2 has attracted great interest in the experiment. However, the detail of the interaction mechanisms between inhibitors and SIRT2 is not well understood. In our study, we synthesised SIRT2 selective inhibitor TPN0_C7 as a model of the proper inhibitor of SIRT2. With the molecular dynamics (MD) simulations, we found that the hydrophobic interactions play the important roles between the inhibitors and SIRT2. According to the conformation character of the inhibitor TPN0_C7, we also explored the natural product, Ge Gen (Puerarol is one of the components.), which is a very effective herb for cancer described in Traditional Chinese Medicine (TCMs) library. Dramatically, we found that the structurally similar inhibitors, Puerarol and TPN0_C7, have the similar binding sites on SIRT2. The hydrophobic and π-π interactions between inhibitors and SIRT2 are important during the progress of the dynamic simulations. In summary, our study uncovers the interaction mechanisms between the inhibitors and SIRT2 at atom level, which may provide clues to explore more proper inhibitors from TCMs.

中文翻译：

---

分子动力学模拟揭示了抑制剂与 SIRT2 在原子水平上相互作用的机制

摘要 Sirtuins 是组蛋白脱乙酰酶家族的成员，参与多种细胞功能并在癌症中发挥密切作用。探索合适的SIRT2抑制剂引起了实验的极大兴趣。然而，抑制剂与 SIRT2 之间相互作用机制的细节尚不清楚。在我们的研究中，我们合成了 SIRT2 选择性抑制剂 TPN0_C7 作为合适的 SIRT2 抑制剂模型。通过分子动力学 (MD) 模拟，我们发现疏水相互作用在抑制剂和 SIRT2 之间起重要作用。根据抑制剂TPN0_C7的构象特征，我们还探索了天然产物葛根（葛根素是其中的一种成分），这是一种非常有效的中草药（TCMs）库中描述的癌症草药。引人注目的是，我们发现结构相似的抑制剂 Puerarol 和 TPN0_C7 在 SIRT2 上具有相似的结合位点。抑制剂和 SIRT2 之间的疏水性和 π-π 相互作用在动态模拟过程中很重要。总之，我们的研究揭示了抑制剂与 SIRT2 在原子水平上的相互作用机制，这可能为从中药中探索更合适的抑制剂提供线索。