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化学学报
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化学学报 ›› 2007, Vol. 65 ›› Issue (16): 1693-1701. 上一篇    下一篇

研究论文

酮醇酸还原异构酶(KARI)与其抑制剂间相互作用的分子模拟研究

陈沛全1,2, 刘幸海1,2, 孙宏伟3,4, 王宝雷1,2, 李正名*,1,2,4, 赖城明2,3   

  1. (1南开大学元素有机化学研究所 天津 300071)
    (2南开大学元素有机化学国家重点实验室 天津 300071)
    (3南开大学化学系 天津 300071)
    (4南开大学科学计算研究所 天津 300071)
  • 投稿日期:2007-01-22 修回日期:2007-03-19 发布日期:2007-08-28
  • 通讯作者: 李正名

Molecular Simulation Studies of Interactions between Ketol-acid Reductoisomerase and Its Inhibitors

CHEN Pei-Quan1,2; LIU Xing-Hai1,2; SUN Hong-Wei3,4; WANG Bao-Lei1,2; LI Zheng-Ming*,1,2,4; LAI Cheng-Ming2,3   

  1. (1 Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071)
    (2 State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071)
    (3 Department of Chemistry, Nankai University, Tianjin 300071)
    (4 Institute of Scientific Computing, Nankai University, Tianjin 300071)
  • Received:2007-01-22 Revised:2007-03-19 Published:2007-08-28
  • Contact: LI Zheng-Ming

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被引次数

7 | 2

采用MCCE, Autodock及密度泛函方法对酮醇酸还原异构酶(KARI)与其抑制剂间相互作用进行了研究. 计算结果表明, KARI活性位点中的Mg2＋在活性位点残基的离子化状态、活性位点的静电性质以及与抑制剂结合等方面起重要的作用; 同时, 抑制剂在结合方式、前线轨道布居及静电势等方面与酶促反应中间体(HOIV)具有一定程度的相似性; 可电离的羧基是当前发现的靶向KARI抑制剂一个重要的结构特征, 进一步推广可认为潜在的抑制剂应该拥有可电离成负电荷的功能团. 在药物设计中考虑到以上结论, 将有利于发现和改造靶向KARI的抑制剂.

关键词: 酮醇酸还原异构酶(KARI), 抑制剂, Possion-Boltzmann方程, 分子对接, 密度泛函理论

The interactions between ketol-acid reductoisomerase (KARI) and its inhibitors were studied by a series of molecular simulation techniques such as MCCE, Autodock and density functional theory. The calculated results indicated that Mg2＋ ions at the active site played important roles in determining the ionization states of the residues at the active site, electrostatic properties of the active site and ligand binding. The potential inhibitors are similar in the binding mode of KARI, population of the frontier orbitals and electrostatic potentials. The results also identified the ionizable carboxyl groups as a key structural feature for inhibition of KARI. Based on this conclusion, it was further deduced that the potential inhibitors probably had an ionizable group that could release proton and be negatively charged. The conclusions of present study will provide valuable information for designing further potent KARI inhibitors prior to their synthesis.

Key words: ketol-acid reductoisomerase (KARI), inhibitor, Possion-Boltzmann equation, molecular docking, density functional theory