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Abstract：
The overexpression of histone deacetylase 8 (HDAC8) causes several diseases, and the selective inhibition of HDAC8 has been touted as a promising therapeutic strategy due to its fewer side effects. However, the mechanism of HDAC8 selective inhibition remains unclear. In this study, flexible docking and in silico mutation were used to explore the structural change of methionine (M274) during HDAC8 binding to inhibitors, along with the reason for this change. Meanwhile, steered and conventional molecular dynamics simulations were employed to explore the stability of the structural change. The findings suggest that M274 acts as a \"switch\" to control the exposure of the HDAC8-selective pocket. The structure of M274 changes from flipped-out to flipped-in only when L-shaped inhibitors bind to HDAC8. This structural change forms a groove that allows these inhibitors to enter the selective pocket. In other HDACs, a leucine residue replaces M274 in situ, and the same structural change is not observed. The findings reveal the mechanism of selective HDAC8 inhibition and provide guidance for the development of novel selective inhibitors.
摘要：
组蛋白去乙酰化酶8(HDAC8)的过度表达可引起多种疾病,和HDAC8的选择性抑制已被吹捧为一个有前途的治疗策略，由于其副作用少。然而,HDAC8选择性抑制的机制尚不清楚。在这项研究中,柔性对接和模拟突变用于探索HDAC8与抑制剂结合过程中甲硫氨酸（M274）的结构变化，以及这种变化的原因。同时,采用转向和常规分子动力学模拟来探索结构变化的稳定性。研究结果表明，M274充当“开关”来控制HDAC8选择性口袋的暴露。仅当L形抑制剂与HDAC8结合时，M274的结构才从翻转变为翻转。这种结构变化形成允许这些抑制剂进入选择性口袋的凹槽。在其他HDAC中，亮氨酸残基在原位取代M274，并且没有观察到相同的结构变化。研究结果揭示了HDAC8的选择性抑制机制，为新型选择性抑制剂的开发提供了指导。
