物理化学学报 >> 2014, Vol. 30 >> Issue (2): 371-381.doi: 10.3866/PKU.WHXB201312192

生物物理化学 上一篇    下一篇

靛玉红类CDK1抑制剂的同源模建、分子对接及3D-QSAR研究

张青青1, 姚其正1, 张生平1, 毕乐明1, 周之光1, 张骥2   

  1. 1 中国药科大学药学院, 南京210009;
    2 中国药科大学物理化学教研室, 南京210009
  • 收稿日期:2013-10-29 修回日期:2013-12-19 发布日期:2014-01-23
  • 通讯作者: 姚其正, 张骥 E-mail:jzhang@cpu.edu.cn;qz_yao@aliyun.com
  • 基金资助:

    国家“重大新药创制”科技重大专项(2009ZX09103-149)资助

Homology Modeling, Molecular Docking, and 3D-QSAR of Indirubin Analogues as CDK1 Inhibitors

ZHANG Qing-Qing1, YAO Qi-Zheng1, ZHANG Sheng-Ping1, BI Le-Ming1, ZHOU Zhi-Guang1, ZHANG Ji2   

  1. 1 School of Pharmacy, China Pharmaceutical University, Nanjing 210009, P. R. China;
    2 Department of Physical Chemistry, China Pharmaceutical University, Nanjing 210009, P. R. China
  • Received:2013-10-29 Revised:2013-12-19 Published:2014-01-23
  • Contact: YAO Qi-Zheng, ZHANG Ji E-mail:jzhang@cpu.edu.cn;qz_yao@aliyun.com
  • Supported by:

    The project was supported by the National Key Subject of Drug Innovation, China (2009ZX09103-149).

摘要:

细胞周期蛋白依赖性激酶1的异常表达会导致G2期的停滞及多种肿瘤的发生,故CDK1近年来已成为一个理想的治疗靶点. 本文以细胞分裂调控蛋白2的同源体为模板,同源模建了CDK1的结构,并与靛玉红类小分子抑制剂进行分子对接. 分别运用三种叠合方法进行分子叠合,并在此基础上采用Sybyl 7.1中的比较分子场分析(CoMFA)模块及Discovery Studio 3.0中的三维定量构效关系(3D-QSAR)模块(以下简称为DS)分别建立了3D-QSAR模型. 其中,将分子对接叠合与公共骨架叠合联合运用的叠合方法所得3D-QSAR模型的评价参数是最佳的(CoMFA:q2=0.681,r2=0.909,rpred.2=0.836; DS:q2=0.579,r2=0.971,rpred.2=0.795,其中q2为交叉验证系数,r2为非交叉验证系数). 本文的研究结果在对靛玉红类小分子进行结构修饰设计出新的CDK1抑制剂方面,可提供重要的理论基础.

关键词: 细胞周期蛋白依赖性激酶1, 靛玉红, 3D-QSAR, 比较分子场分析, 同源模建

Abstract:

The abnormal expression of cyclin-dependent kinase 1 (CDK1) leads to stagnation of the G2 phase and a variety of tumors. Therefore, CDK1 has been reported recently as an ideal cell cycle target for cancer drug discovery. In this paper, we use the cell division control protein 2 homolog as a template to homologically model the protein of CDK1 that is subsequently docked with the inhibitors of indirubin analogues. Three molecular alignment methods were used, and the corresponding three- dimensional quantitative structure-activity relationship (3D-QSAR) models were built using the comparative molecular field analysis (CoMFA) protocol in Sybyl 7.1 and the 3D-QSAR protocol (abbreviated for DS) in Discovery Studio 3.0. It was found that the molecular alignment method combining molecular docking with public template is most suitable for building the 3D-QSARmodels, and shows the best calculated results (CoMFA: q2=0.681, r2=0.909, and rpred.2=0.836; DS: q2= 0.579, r2=0.971, and rpred.2=0.795, where q2 denotes the cross-validated correlation coefficient and r2 denotes the non- cross- validated correlation coefficient). This paper may provide significant theoretical foundation for designing novel CDK1 inhibitors by carrying out structural modifications of indirubin analogues.

Key words: Cyclin-dependent kinase 1, Indirubin, 3D-QSAR, CoMFA, Homology modeling

MSC2000: 

  • O641