物理化学学报 >> 2011, Vol. 27 >> Issue (08): 1831-1838.doi: 10.3866/PKU.WHXB20110808

理论与计算化学 上一篇    下一篇

咪唑甘油磷酸酯脱水酶与含氮杂环磷酸酯类抑制剂作用方式的分子模拟

申涛1, 杜凤沛1, 刘婷1, 姚广伟1, 吴峥1, 方萌萌1, 徐筱杰2, 路慧哲1   

  1. 1. 中国农业大学理学院, 北京 100193;
    2. 北京大学化学与分子工程学院, 北京 100871
  • 收稿日期:2011-01-26 修回日期:2011-05-05 发布日期:2011-07-19
  • 通讯作者: 路慧哲 E-mail:luhz2008@yahoo.com.cn
  • 基金资助:

    国家自然科学基金(20972184)和中央高校基本科研业务费专项资金(2009JS38,2011JS036)资助项目

Molecular Simulation of the Interaction between Imidazole Glycerol Phosphate Dehydrase and Nitrogen-Containing Heterocyclic Phosphate Inhibitors

SHEN Tao1, DU Feng-Pei1, LIU Ting1, YAO Guang-Wei1, WU Zheng1, FANG Meng-Meng1, XU Xiao-Jie2, LU Hui-Zhe1   

  1. 1. Institute of Science and Technology, China Agricultural University, Beijing 100193, P. R. China;
    2. Institute of Chemistry and Molecular Engineering, Peking University, Beijing 100871, P. R. China
  • Received:2011-01-26 Revised:2011-05-05 Published:2011-07-19
  • Contact: LU Hui-Zhe E-mail:luhz2008@yahoo.com.cn
  • Supported by:

    The project was supported by the National Natural Science Foundation of China (20972184) and Chinese Universities Scientific Fund (2009JS38,2011JS036).

摘要:

国际上依据咪唑甘油磷酸酯脱水酶(IGPD)底物结构筛选, 成功获得了一系列含氮杂环磷酸酯类化合物作为IGPD抑制剂, 然而IGPD与含氮杂环磷酸酯类抑制剂间的作用模式尚不清楚. 本研究利用Gaussian 03程序, 基于密度泛函理论B3LYP方法, 选择6-31G**基组优化含氮杂环磷酸酯类化合物, 在确定其稳定构象的基础上利用分子对接、力学优化构建IGPD与其含氮杂环磷酸酯类抑制剂相互作用的复合物结构, 基于化合物的电子结构(前线轨道能级及组成、原子电荷、自然键轨道等)、复合物的空间结构(抑制剂识别IGPD的功能域、分子间氢键、van der Waals相互作用等)探讨了IGPD与含氮杂环磷酸酯类抑制剂作用方式, 确定了含氮杂环电荷分布、磷酸根离子电荷分布、前线轨道LUMO能级是影响抑制剂活性的内在因素, 为进一步筛选、优化高效的新型除草剂提供了重要信息.

关键词: 咪唑甘油磷酸酯脱水酶, 抑制剂, 分子对接, 力学优化, 密度泛函理论, 前线轨道

Abstract:

A series of nitrogen-containing heterocyclic compounds as imidazole glycerol phosphate dehydrase (IGPD) inhibitors were successfully screened based on IGPD substrates; however, the mechanism is not clear. In this study, the B3LYP density functional theory method with the 6-31G** basis set as implemented in the Gaussian 03 program was selected to optimize the nitrogen-containing heterocyclic phosphates. These complex structures were constructed using molecular docking and optimization. The mode of interaction was discussed with regards to their electronic structures (frontier orbital energies and composition, the atomic charges, the natural bond orbital, etc.) and complex spatial structures (recognition functional domains of the inhibitor of IGPD, intermolecular hydrogen bonding, van der Waals interactions, etc.). The charge distribution of the nitrogen-containing heterocycle, the phosphate ion charge distribution, and the frontier orbital LUMO energy levels of the inhibitor were determined to be intrinsic factors that affect inhibitor activity. The conclusion of our study will provide valuable information for the screening and optimization of new herbicides targeted at IGPD.

Key words: Imidazole glycerol phosphate dehydratase, Inhibitor, Molecular docking, Mechanical optimization, Density functional theory, Frontier orbital

MSC2000: 

  • O641