五元杂环并嘧啶类胸苷酸合成酶抑制剂的构效关系和分子对接  

QSAR and Molecular Docking on Five-Membered Heterocyclopyrimidines as Thymidylate Synthase Inhibitors

作　　者：康从民[1] 赵绪浩[1] 王新宇[1] 程家高[2] 吕英涛[1] 

机构地区：[1]青岛科技大学化工学院,山东青岛266042 [2]华东理工大学药学院,上海市化学生物学重点实验室,上海200237

出　　处：《物理化学学报》2013年第2期431-438,共8页Acta Physico-Chimica Sinica

基　　金：国家自然科学基金(21072111;21172070;21272131);山东省自然科学基金(ZR2011BM 015)资助项目~~

摘　　要：用比较分子场分析法(CoMFA)和比较分子相似性指数分析法(CoMSIA)研究了38个五元杂环并嘧啶衍生物类胸苷酸合成酶抑制剂的三维定量构效关系(3D-QSAR),建立了相关预测模型.CoMFA和CoMSIA模型的交互验证相关系数q^2分别为0.662和0.672、非交互验证相关系数R^2分别为0.921和0.884、外部交互验证相关系数Q_(ext^2)分别为0.85和0.81.分子对接得到的结合模式与三维定量构效关系得到的结果一致.结果表明这两种模型都具有良好的预测能力,可应用于指导化合物的设计和结构修饰,为进一步设计新型胸苷酸合成酶抑制剂提供了理论依据.The three-dimensional quantitative structure-activity relationships （3D-QSAR） were established for 38 five-membered heterocyclopyrimidine thymidylate synthase inhibitors by using comparative molecular field analysis （CoMFA） and comparative similarity indices analysis （CoMSIA） techniques. With the CoMFA model, the cross-validated value （q2） was 0.662, the non-cross-validated value （R2） was 0.921, and the external cross-validated value （Qθxt2） was 0.85. And with the CoMSIA model, the corresponding q2, R2, and Qθxt2, values were 0.672, 0.884, and 0.81, respectively. The mode of action obtained by molecular docking was in agreement with the 3D-QSAR results. The results revealed that both models have good predictive capability to guide the design and structural modification of homologic compounds. Furthermore, these results also establish a base level for further research and development of new thymidylate synthase inhibitors.

关 键 词：五元芳杂环并嘧啶衍生物 三维定量构效关系 比较分子场分析法 比较分子相似性指数分析法 分子对接 

分 类 号：TQ460.1[化学工程—制药化工]