芳基磺酰胺类丙酮酸激酶M2激动剂的基于多复合物的药效团模型和定量构效关系  

Multicomplex-Based Pharmacophore and QSAR of Aryl-Sulfamides as Pyruvate Kinase M2 Activators

作　　者：陈正军[1] 蒋庆琳[2] 何谷[1,3] 韩波[4] 郭丽[1] 

机构地区：[1]四川大学华西药学院,成都610041 [2]成都医学院药学系,成都610500 [3]四川大学华西医院,生物治疗国家重点实验室,成都610041 [4]成都中医药大学药学院,成都611137

出　　处：《物理化学学报》2013年第8期1793-1803,共11页Acta Physico-Chimica Sinica

基　　金：国家自然科学基金(30901837;81001357;81273471)资助项目~~

摘　　要：丙酮酸激酶M2(PKM2)是肿瘤治疗中最具发展潜力的靶点之一.本文以一系列丙酮酸激酶M2-激动剂复合物的晶体结构为基础,采用基于多复合物的药效团(MCBP)方法产生了PKM2的药效团模型.并使用该药效团模型产生了62个芳基磺酰胺类PKM2激动剂的活性构象和分子叠合,通过三维定量构效关系(3D-QSAR)方法研究了该类PKM2激动剂与PKM2蛋白的相互作用,并建立了相关预测模型.比较分子场分析法(CoMFA)和比较分子相似性指数分析法(CoMSIA)模型的交互验证相关系数q2分别为0.545和0.653,非交互验证相关系数r2分别为0.966和0.987.本研究为进一步结构优化、设计和合成新型的PKM2激动剂提供了理论依据.Pyruvate kinase M2 （PKM2） is well-known as a potential target for cancer therapy. In this study, the multicomplex-based pharmacophore （MCBP）-guided method was used to generate a comprehensive pharmacophore of PKM2 kinase based on a collection of crystal structures of PKM2- activator complex. This model was successfully used to identify the bioactive conformation and align 62 structurally diverse aryl-sulfamide derivatives. Quantitative structure-activity relationship （QSAR） analyses were performed on these PKM2 activators based on MCBP-guided alignment. With the comparative molecular field analysis （CoMFA） model, the cross-validated value （q2） was 0.545, and the non-cross- validated value （r2） was 0.966. With the comparative molecular similarity indices analysis （CoMSIA） model, q2 and r2 were 0.653 and 0.987. These results may provide important information for further design of novel PKM2 activators.

关 键 词：芳基磺酰胺衍生物 丙酮酸激酶 药效团 比较分子场分析 比较分子相似性指数分析 

分 类 号：TQ460.1[化学工程—制药化工]