物理化学学报 >> 2013, Vol. 29 >> Issue (02): 431-438.doi: 10.3866/PKU.WHXB201211151

生物物理化学 上一篇    下一篇

五元杂环并嘧啶类胸苷酸合成酶抑制剂的构效关系和分子对接

康从民1, 赵绪浩1, 王新宇1, 程家高2, 吕英涛1   

  1. 1 青岛科技大学化工学院, 山东 青岛 266042;
    2. 华东理工大学药学院, 上海市化学生物学重点实验室, 上海 200237
  • 收稿日期:2012-08-27 修回日期:2012-11-14 发布日期:2013-01-14
  • 通讯作者: 吕英涛 E-mail:lvyingtao@qust.edu.cn
  • 基金资助:

    国家自然科学基金(21072111, 21172070, 21272131)和山东省自然科学基金(ZR2011BM015)资助项目

QSAR and Molecular Docking on Five-Membered Heterocyclopyrimidines as Thymidylate Synthase Inhibitors

KANG Cong-Min1, ZHAO Xu-Hao1, WANG Xin-Yu1, CHENG Jia-Gao2, LÜ Ying-Tao1   

  1. 1 College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, Shandong Province, P. R. China;
    2 Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, P. R. China
  • Received:2012-08-27 Revised:2012-11-14 Published:2013-01-14
  • Supported by:

    The project was supported by the National Natural Science Foundation of China (21072111, 21172070, 21272131) and Shandong Provincial Natural Science Foundation, China (ZR2011BM015).

摘要:

用比较分子场分析法(CoMFA)和比较分子相似性指数分析法(CoMSIA)研究了38个五元杂环并嘧啶衍生物类胸苷酸合成酶抑制剂的三维定量构效关系(3D-QSAR), 建立了相关预测模型. CoMFA和CoMSIA模型的交互验证相关系数q2分别为0.662和0.672、非交互验证相关系数R2分别为0.921和0.884、外部交互验证相关系数Qext2分别为0.85和0.81. 分子对接得到的结合模式与三维定量构效关系得到的结果一致. 结果表明这两种模型都具有良好的预测能力, 可应用于指导化合物的设计和结构修饰, 为进一步设计新型胸苷酸合成酶抑制剂提供了理论依据.

关键词: 五元芳杂环并嘧啶衍生物, 三维定量构效关系, 比较分子场分析法, 比较分子相似性指数分析法, 分子对接

Abstract:

The three-dimensional quantitative structure-activity relationships (3D-QSAR) were established for 38 five-membered heterocyclopyrimidine thymidylate synthase inhibitors by using comparative molecular field analysis (CoMFA) and comparative similarity indices analysis (CoMSIA) techniques. With the CoMFA model, the cross-validated value (q2) was 0.662, the non-cross-validated value (R2) was 0.921, and the external cross-validated value (Qext2) was 0.85. And with the CoMSIA model, the corresponding q2, R2, and Qext2 values were 0.672, 0.884, and 0.81, respectively. The mode of action obtained by molecular docking was in agreement with the 3D-QSAR results. The results revealed that both models have good predictive capability to guide the design and structural modification of homologic compounds. Furthermore, these results also establish a base level for further research and development of new thymidylate synthase inhibitors.

Key words: Five-membered heterocyclopyrimidine derivative, Three dimensional quantitative structure-activity relationship, Comparative molecular field analysis, Comparative molecular similarity indices analysis, Molecular docking

MSC2000: 

  • O641