高等学校化学学报 ›› 2018, Vol. 39 ›› Issue (7): 1540-1548.doi: 10.7503/cjcu20170657

• 物理化学 • 上一篇    下一篇

分子动力学模拟研究Fedratinib-JAK2/JAK3选择性

刘海春1, 卢帅1, 张艳敏1, 周伟能1, 尹凌枫1, 朱露1, 赵珺楠1, 陆涛1,2(), 陈亚东1()   

  1. 1. 中国药科大学理学院, 南京 211198
    2. 中国药科大学天然药物活性组分与药效国家重点实验室, 南京 210009
  • 收稿日期:2017-09-29 出版日期:2018-07-10 发布日期:2018-06-19
  • 作者简介:联系人简介: 陆 涛, 男, 博士, 教授, 主要从事新药开发研究. E-mail: lutao@cpu.edu.cn; 陈亚东, 男, 博士, 教授, 主要从事药物分子设计与合成研究. E-mail:ydchen@cpu.edu.cn
  • 基金资助:
    国家自然科学基金(批准号: 21572273)资助.

Molecular Dynamics Simulation of the Selectivity of Fedratinib Complex with JAK2/JAK3

LIU Haichun1, LU Shuai1, ZHANG Yanmin1, ZHOU Weineng1, YIN Lingfeng1, ZHU Lu1, ZHAO Junnan1, LU Tao1,2,*(), CHEN Yadong1,*()   

  1. 1.School of Basic Science, China Pharmaceutical University, Nanjing 211198, China
    2.State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
  • Received:2017-09-29 Online:2018-07-10 Published:2018-06-19
  • Contact: LU Tao,CHEN Yadong E-mail:lutao@cpu.edu.cn;ydchen@cpu.edu.cn
  • Supported by:
    † Supported by the National Natural Science Foundation of China(No. 21572273).

摘要:

通过动力学模拟获得JAK2高选择性抑制剂Fedratinib在JAK2和JAK3激酶中的结合构象, 结合自由能的计算结果表明Fedratinib在JAK2中更稳定. 将能量分解到结合位点氨基酸, 分析发现当分子在JAK2中占据P-loop区的疏水口袋, 并与附近Arg980和Asp994等氨基酸形成氢键时, 可以增加相对于JAK2的选择性.

关键词: JAK2抑制剂, 选择性, 分子动力学, 自由结合能

Abstract:

Molecular dynamic(MD) simulation was carried out in both JAK2-Fedratinib and JAK3-Fedratinib complex, respectively. Binding free energy was calculated in utilize the trajectory of MD. The results indicated the energy of JAK2-Fedratinib was lower than that of JAK3-Fedratinib, which demonstrate the different enzyme activity in two kinase. When binding free energy was decomposed into each residue of binding site, it could be found that when molecule occupies the pockets below P-loop and form H-bonds with residues nearby the selectivity for JAK2 over JAK3 may be highlighted. The results can provide insights for further development of more potent and selective JAK2 inhibitors.

Key words: JAK2 inhibitor, Selectivity, Molecular dynamic, Binding free energy

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