高等学校化学学报 ›› 2010, Vol. 31 ›› Issue (2): 374.

• 研究论文 • 上一篇    下一篇

Apicidin选择性抑制ClassⅠ HDACs分子动力学研究

李晓晖1, 赵俊伟1, 滕虎1, 西野宪和2, 修志龙1   

  1. 1. 大连理工大学环境与生命学院, 大连 116024;
    2. 日本九州工业大学大学院生命体工学研究科, 北九州 808-0196
  • 收稿日期:2009-03-17 出版日期:2010-02-10 发布日期:2010-02-10
  • 通讯作者: 修志龙, 男, 博士, 教授, 主要从事生物化工研究. E-mail: zhlxiu@dlut.edu.cn; 李晓晖, 女, 硕士, 副教授, 主要从事多肽药物化学研究. E-mail: lxhxh@dlut.edu.cn
  • 基金资助:

    国家“八六三”计划项目(批准号: 2007AA021604)资助.

Selective Inhibition Study of Apicidin Towards Class I HDACs by Molecular Dynamics Simulation

LI Xiao-Hui1*, ZHAO Jun-Wei1, TENG Hu1, NISHINO Norikazu2, XIU Zhi-Long1*   

  1. 1. School of Environment and Biological Science and Technology, Dalian University of Technology, Dalian 116024, China;
    2. Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, Kitakyushu 808-0196, Japan

  • Received:2009-03-17 Online:2010-02-10 Published:2010-02-10
  • Contact: XIU Zhi-Long. E-mail: zhlxiu@dlut.edu.cn; LI Xiao-Hui. E-mail: lxhxh@dlut.edu.cn
  • Supported by:

    国家“八六三”计划项目(批准号: 2007AA021604)资助.

摘要:

采用模拟方法研究组蛋白脱乙酰酶抑制剂(Apicidin)选择性抑制组蛋白去乙酰化酶(Histone deacetylases, HDACs)中的HDAC1和HDAC8. 通过HDAC8晶体结构同源模建HDAC1三维结构模型, 将Apicidin分别与HDAC1和HDAC8对接并进行分子动力学模拟, 结果表明, HDAC1活性口袋入口处的Arg270是Apicidin-HDAC1形成稳定结构的重要因素; HDAC1中Tyr303及His178与Apicidin形成2个持续存在的氢键, 而在HDAC8中未发现, 这是Apicidin选择性抑制HDAC1高于HDAC8的另一重要原因.

关键词: 组蛋白脱乙酰酶抑制剂; 组蛋白去乙酰化酶(HDACs); 分子动力学; 同源模建; 分子对接

Abstract:

The selective inhibitory activity of cyclic tetrapeptides apicidin towards class I histone deacetylases(HDACs) was studied by molecular dynamics simulation. The 3D structure of HDAC1 was constructed by homology modeling using the X-ray structure of HDAC8 as template. Furthermore, the 3500 ps molecular dynamics simulations were performed on both apicidin-HDAC1 and apicidin-HDAC8 complexes, which were obtained by molecular docking. As a result, the Arg270 locating at the entrance of the HDAC1 active pocket played a crucial role in forming stable interactions with apicidin. There were two lasting hydrogen bonds between apicidin and HDAC1 during the molecular dynamics simulation, while none between apicidin and HDAC8. This difference could be another important reason for the high inhibitory activity of apicidin to HDAC1.

Key words: Apicidin; Histone deacetylase; Molecular dynamics; Homology modeling; Molecular docking

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