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靛玉红类CDK1抑制剂的同源模建、分子对接及3D-QSAR研究
引用本文:张青青,姚其正,张生平,毕乐明,周之光,张骥. 靛玉红类CDK1抑制剂的同源模建、分子对接及3D-QSAR研究[J]. 物理化学学报, 2014, 30(2): 371-381. DOI: 10.3866/PKU.WHXB201312192
作者姓名:张青青  姚其正  张生平  毕乐明  周之光  张骥
作者单位: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
基金项目:国家“重大新药创制”科技重大专项(2009ZX09103-149)资助
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  
收稿时间:2013-10-29
修稿时间:2013-12-19

Homology Modeling,Molecular Docking,and 3D-QSAR of Indirubin Analogues as CDK1 Inhibitors
ZHANG Qing-Qing,YAO Qi-Zheng,ZHANG Sheng-Ping,BI Le-Ming,ZHOU Zhi-Guang,ZHANG Ji. Homology Modeling,Molecular Docking,and 3D-QSAR of Indirubin Analogues as CDK1 Inhibitors[J]. Acta Physico-Chimica Sinica, 2014, 30(2): 371-381. DOI: 10.3866/PKU.WHXB201312192
Authors:ZHANG Qing-Qing  YAO Qi-Zheng  ZHANG Sheng-Ping  BI Le-Ming  ZHOU Zhi-Guang  ZHANG Ji
Affiliation: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
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.
Keywords:Cyclin-dependent kinase 1  Indirubin  3D-QSAR  CoMFA  Homology modeling
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