物理化学学报 >> 2013, Vol. 29 >> Issue (08): 1793-1803.doi: 10.3866/PKU.WHXB201305152

生物物理化学 上一篇    下一篇

芳基磺酰胺类丙酮酸激酶M2激动剂的基于多复合物的药效团模型和定量构效关系

陈正军1, 蒋庆琳2, 何谷1,3, 韩波4, 郭丽1   

  1. 1 四川大学华西药学院, 成都 610041;
    2 成都医学院药学系, 成都 610500;
    3 四川大学华西医院, 生物治疗国家重点实验室, 成都 610041;
    4 成都中医药大学药学院, 成都 611137
  • 收稿日期:2013-03-11 修回日期:2013-05-14 发布日期:2013-07-09
  • 通讯作者: 何谷 E-mail:hegu@scu.edu.cn
  • 基金资助:

    国家自然科学基金(30901837, 81001357, 81273471)资助项目

Multicomplex-Based Pharmacophore and QSAR of Aryl-Sulfamides as Pyruvate Kinase M2 Activators

CHEN Zheng-Jun1, JIANG Qing-Lin2, HE Gu1,3, HAN Bo4, GUO Li1   

  1. 1 West China School of Pharmacy, Sichuan University, Chengdu 610041, P. R. China;
    2 Department of Pharmacy, Chengdu Medical College, Chengdu 610500, P. R. China;
    3 State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;
    4 School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. China
  • Received:2013-03-11 Revised:2013-05-14 Published:2013-07-09
  • Contact: HE Gu E-mail:hegu@scu.edu.cn
  • Supported by:

    The project was supported by the National Natural Science Foundation of China (30901837, 81001357, 81273471).

摘要:

丙酮酸激酶M2(PKM2)是肿瘤治疗中最具发展潜力的靶点之一. 本文以一系列丙酮酸激酶M2-激动剂复合物的晶体结构为基础, 采用基于多复合物的药效团(MCBP)方法产生了PKM2 的药效团模型. 并使用该药效团模型产生了62个芳基磺酰胺类PKM2激动剂的活性构象和分子叠合, 通过三维定量构效关系(3D-QSAR)方法研究了该类PKM2激动剂与PKM2蛋白的相互作用, 并建立了相关预测模型. 比较分子场分析法(CoMFA)和比较分子相似性指数分析法(CoMSIA)模型的交互验证相关系数q2分别为0.545 和0.653, 非交互验证相关系数r2分别为0.966和0.987. 本研究为进一步结构优化、设计和合成新型的PKM2激动剂提供了理论依据.

关键词: 芳基磺酰胺衍生物, 丙酮酸激酶, 药效团, 比较分子场分析, 比较分子相似性指数分析

Abstract:

Pyruvate kinase M2 (PKM2) is well-known as a potential target for cancer therapy. In this study, the multicomplex-based pharmacophore (MCBP)-guided method was used to generate a comprehensive pharmacophore of PKM2 kinase based on a collection of crystal structures of PKM2- activator complex. This model was successfully used to identify the bioactive conformation and align 62 structurally diverse aryl-sulfamide derivatives. Quantitative structure-activity relationship (QSAR) analyses were performed on these PKM2 activators based on MCBP-guided alignment. With the comparative molecular field analysis (CoMFA) model, the cross-validated value (q2) was 0.545, and the non-crossvalidated value (r2) was 0.966. With the comparative molecular similarity indices analysis (CoMSIA) model, q2 and r2 were 0.653 and 0.987. These results may provide important information for further design of novel PKM2 activators.

Key words: Aryl-sulfamide derivative, Pyruvate kinase, Pharmacophore, Comparative molecular field analysis, Comparative molecular similarity indices analysis

MSC2000: 

  • O641