物理化学学报 >> 2004, Vol. 20 >> Issue (06): 569-572.doi: 10.3866/PKU.WHXB20040603

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HDAC对接研究:苯甲酰胺类抑制剂结合方式推测

谢爱华;李伯玉;廖晨钟;李志斌;鲁先平;石乐明;周家驹   

  1. 中国科学院过程工程研究所,北京 100080;深圳微芯生物科技有限公司,深圳 518057
  • 收稿日期:2004-02-24 修回日期:2004-03-23 发布日期:2004-06-15
  • 通讯作者: 周家驹 E-mail:jjzhou@lcc.icm.ac.cn

Docking Study of HDAC Implication for Benzamide Inhibitors Binding Mode

Xie Ai-Hua;Li Bo-Yu;Liao Chen-Zhong;Li Zhi-Bin;Lu Xian-Ping;Shi Le-Ming;Zhou Jia-Ju   

  1. Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100080; 1Chipscreen Biosciences, Limited, Shenzhen 518057
  • Received:2004-02-24 Revised:2004-03-23 Published:2004-06-15
  • Contact: Zhou Jia-Ju E-mail:jjzhou@lcc.icm.ac.cn

摘要: 通过计算机模拟的对接过程研究,发现了MS-275— 一种苯甲酰胺类的组蛋白去乙酰酶(HDAC)抑制剂与酶的可能的全新结合方式.这种结合方式与已经阐明的组蛋白去乙酰酶类似蛋白(HDLP)与曲古柳菌素A(trichostatin A, TSA)和suberoylanilide hydroxamic acid(SAHA)形成的复合物晶体结构中配体与酶的作用方式完全不同.从对接结果看,MS-275的作用靶点在酶活性口袋的最狭窄部位,而不是直接作用于锌离子.这似乎能够解释MS-275的低毒性特点,并且为设计和筛选全新的HDAC抑制剂提供了新思路.

关键词: 组蛋白去乙酰酶(HDAC), 组蛋白去乙酰酶类似蛋白(HDLP), 曲古柳菌素A(TSA), 对接, MS-275

Abstract: The paper proposed a possible binding mode of MS-275, a benzamide histone deacetylase (HDAC) inhibitor, to HDAC by intensive docking study. This binding mode is different from those observed in the crystal structure of complexes formed by a histone deacetylase-like protein (HDLP) with trichostatin A (TSA) or suberoylanilide hydroxamic acid (SAHA). The docking result implicates that the main target of MS-275 is the narrowest part of HDAC active pocket. It seems to be able to explain the low toxicity of MS-275 and provides new insights on the design of novel HDAC inhibitors.

Key words: Histone deacetylase(HDAC), Histone deacetylase like protein(HDLP),  Trichostatin A(TSA), Docking, MS-275