How Does Chirality Determine the Selective Inhibition of Histone Deacetylase 6? A Lesson from Trichostatin A Enantiomers Based on Molecular Dynamics
How Does Chirality Determine the Selective Inhibition of Histone Deacetylase 6? A Lesson from Trichostatin A Enantiomers Based on Molecular Dynamics
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手性如何决定组蛋白脱乙酰酶 6 的选择性抑制？
DOI：
10.1021/acschemneuro.8b00729
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发表时间：
2019
影响因子：
5
通讯作者：
Zhu Feng
中科院分区：
文献类型：
--
作者：
Zhang Yang;Ying Jun Biao;Hong Jia Jun;Li Feng Chen;Fu Ting Ting;Yang Feng Yuan;Zheng Guo Xun;Yao Xiao Jun;Lou Yan;Qiu Yunqing;Xue Wei Wei;Zhu Feng
组蛋白去乙酰化酶6（HDAC 6）在多种神经系统疾病中起关键作用，这使得它成为治疗阿尔茨海默病、帕金森病和记忆/学习障碍的有吸引力的药物靶点。HDAC 6抑制剂（sHDAC 6 Is）的选择性被广泛认为易受其Cap基团的大小和其接头或锌结合基团的物理化学性质的影响，这使得发现新的sHDAC 6 Is极其困难。随着曲古抑菌素A（TSA）对映体间选择性差异的发现，TSA的Cap和linker之间连接单元的手性对其选择性有很大的影响。然而，强调（S）-TSA的选择性的机制仍然是难以捉摸的，并且手性将选择性（S）-TSA转换为非选择性（R）-TSA的方式是未知的。在这项研究中，多种计算方法共同应用于探索，验证，并区分两个TSA对映体在HDACs（特别是HDAC 6）在原子水平上的结合模式。首先，发现环3中的两个非保守残基（HDAC 1/6中的G200/M205和Y197/F202）和疏水结合口袋深处的四个保守残基是（S）-TSA对HDAC 6的选择性的决定性残基。提出了（S）-TSA对HDAC 6选择性的一种新机制，即HDAC 6中两个非保守残基F202和M205的触发作用和随后（S）-TSA深入HDAC 6疏水结合口袋的改进匹配作用。本研究以TSA对映体作为分子探针，探讨sHDAC 6 Is选择性的机制。由于它们在（S）-TSA对HDAC 6的选择性中的决定性作用，HDAC 6中的F202和M205在发现新的sHDAC 6 Is时应特别考虑。
Histone deacetylase 6 (HDAC6) plays a key role in a variety of neurological disorders, which makes it attractive drug target for the treatment of Alzheimer’s disease, Parkinson’s disease, and memory/learning impairment. The selectivity of HDAC6 inhibitors (sHDAC6Is) are widely considered to be susceptible to the sizes of their Cap group and the physicochemical properties of their linker or zinc-binding group, which makes the discovery of new sHDAC6Is extremely difficult. With the discovery of the distinct selectivity between Trichostatin A (TSA) enantiomers, the chirality residing in the connective units between TSA’s Cap and linker shows a great impact on its selectivity. However, the mechanism underlining (S)-TSA’s selectivity is still elusive, and the way chirality switches the selective (S)-TSA to nonselective (R)-TSA is unknown. In this study, multiple computational approaches were collectively applied to explore, validate, and differentiate the binding modes of two TSA enantiomers in HDACs (especially the HDAC6) at atomic level. First, two nonconservative residues (G200/M205 and Y197/F202 in HDAC1/6) in loop3 and four conservative residues deep inside the hydrophobic binding pocket were discovered as the decisive residues of (S)-TSA’s selectivity toward HDAC6. Then, a novel mechanism underlying the selectivity of (S)-TSA toward HDAC6 was proposed, which was composed of the trigger by two nonconservative residues F202 and M205 in HDAC6 and a subsequently improved fit of (S)-TSA deep inside HDAC6’s hydrophobic binding pocket. TSA enantiomers were used as a molecular probe to explore the mechanism underlying sHDAC6Is’ selectivity in this study. Because of their decisive roles in (S)-TSA’s selectivity to HDAC6, both F202 and M205 in HDAC6 should be especially considered in the discovery of novel sHDAC6Is.