噻吩和三唑酮类Chk1抑制剂的特征结构研究  

Study on the Structural Features of Thiophenes and Triazolones as Chk1 Inhibitors

作　　者：吴倩[1] 李丹[1] 赵鑫钰[1] 刘莉[1] 王惠[1] 李燕[2] 

机构地区：[1]潍坊学院化学化工与环境工程学院,潍坊261061 [2]大连理工大学化工学院,大连116024

出　　处：《化学通报》2014年第1期71-76,共6页Chemistry

基　　金：国家自然科学基金项目(21103129);山东省科技发展计划项目(2012YD17007);潍坊市科技发展计划项目(20121299)资助

摘　　要：检验点激酶1(Chk1)是一种丝氨酸/苏氨酸蛋白激酶,可使受损癌细胞发生细胞周期阻滞并促进DNA损伤修复,降低放疗对肿瘤细胞的杀伤作用。抑制Chk1活性可消除细胞周期阻滞,阻碍肿瘤细胞的自我修复,导致其有丝分裂紊乱最终凋亡。本文采用多元线性回归(MLR)和主成分回归分析(PCA)方法,对164个噻吩和三唑酮类Chk1抑制剂分子的698个参数进行回归分析,分别建立定量构效关系预测模型。结果表明,多元线性回归中的逐步回归(stepwise)是最佳建模方法,所建模型的预测能力较强(训练集R=0.85,检验集R=0.88),运用拓扑电荷指数、原子核片段等20个参数直观反映了影响活性的主要因素。此模型的确立对设计和开发新型高效Chk1抑制剂具有指导意义。Checkpoint kinasel （Chk1）, a serine/threonine protein kinase, mediates the cellular response to DNA-damage by leading to cell-cycle arrest, and reduces the therapeutic efficacy of radiotherapy. Inhibition of Chkl has been shown to abrogate DNA damage induced cell cycle arrest, impeding cancer cells to repair themselves and leading to mitotic catastrophe and cell death or apoptosis. In this paper, 698 molecular indices, coming from 164 thiophenes and triazolones as Chkl inhibitors, were regressed by using multiple linear regression （MLR） and principal component regression analysis （PCA） methods, finally ending up with the optimum predictable models. The results showed that stepwise regression analysis was the best regression method. The developed model showed its proper predictability by the independent training set （R = 0.85 ） and test set （ R = 0.88 ） , employing 20 molecular indices, such as topological charge indices, atom-centred fragments, directly reflecting the main factors influencing activity of the inhibitors. This model is helpful for the design and development of new, efficient Chkl inhihitors.

关 键 词：Chk1抑制剂 定量构效关系 多元线性回归 主成分分析 

分 类 号：R914[医药卫生—药物化学]