嘧啶类CDK1激酶抑制剂的三维定量构效关系  

3D-QSAR studies on pyrimidine analogues as cyclin-dependent kinase 1 inhibitors

作　　者：罗海彬[1] 陈国文[1] 邵咏贤[1] 李哲[1] 刘明[1] 刘培庆[1] 

机构地区：[1]中山大学药学院,广州510006

出　　处：《深圳大学学报（理工版）》2012年第5期438-443,共6页Journal of Shenzhen University(Science and Engineering)

基　　金：国家自然科学基金资助项目(21103234);广东省自然科学基金资助项目(S2011030003190)~~

摘　　要：1型细胞周期蛋白依赖性激酶(cyclin-dependent kinase 1,CDK1)在人体内是有效的抗癌作用靶标.使用三维定量构效关系研究方法,包括比较分子场分析法(comparative molecular field analysis,CoM-FA)和比较分子相似性指数分析法(comparative molecular similarity indices analysis,CoMSIA),分析23个CDK1激酶抑制剂的分子结构与生物活性之间的定量关系.相对其他类型电荷,当训练集加载Gasteiger-Huckel电荷时,CoMFA获得一个最优的三维定量构效关系模型,其交叉验证系数q2为0.668,非交叉验证相关系数R2为0.941,表明模型具有较好的预测能力.使用测试集交叉验证说明该模型稳定可靠,模型中立体场贡献率为69.8%,静电场贡献率为30.2%.Cyclin-dependent kinases （CDKs） are serine/threonine kinases, which play significant roles in cell cycle regulation. CDK1 is an anti-cancer target among these CDKs. To identify the quantitative relationships between the molecular structures and their biological affinities of twenty-three CDK1 inhibitors, three dimensional quantitative structure-activity relationships （3D-QSAR） studies were performed by using the comparative molecular field analysis （CoMFA） and comparative molecular similarity indices analysis （CoMSIA） approaches. In the present study, a reasonable CoMFA Region Focus model with the combined steric and electrostatic fields achieved the highest q2 value （q2 = 0. 668, which R2 = 0. 941 ）. This focus model is adequate to account for the inhibitory mechanisms of these inhibitors. The resulting model was further validated by the test-set examinations. In this model, the contributions of the steric and electrostatic fields were 69.8% and 30. 2%, respectively. The results contribute to the rational molecular design of new 2-amino-4-（7-azaindol-3-yl）pyrimidines derivatives with high inhibitory affinities towards CDK1.

关 键 词：药物化学 药物分子设计 三维定量构效关系 1型细胞周期蛋白依赖性激酶 抑制剂 肿瘤治疗 

分 类 号：R914.2[医药卫生—药物化学] TP183[医药卫生—药学]