咪唑[1,2-b]哒嗪类mTOR抑制剂的三维定量构效关系及分子对接研究  

3D-QSAR and Molecular Docking Research of Imidazo[1,2-b]pyridazine Derivatives as mTOR inHibitors

作　　者：王小平 张静[1] 陈成龙 毛蓓蓓 Wang Xiaoping;Zhang Jing;Chen Chenglong;Mao Beibei(College of pharmacy,Shandong University of Chinese Medicine,Jinan 250355,China)

机构地区：[1]山东中医药大学药学院,山东济南250355

出　　处：《山东化工》2021年第12期1-7,共7页Shandong Chemical Industry

基　　金：山东省自然科学基金项目(No:ZR2019BB031);山东省高等学校科技计划项目(No:J18KA266);山东中医药大学大学生研究训练(SRT)计划项目(No:2020054)。

摘　　要：目的:建立咪唑[1,2-b]哒嗪类mTOR抑制剂的三维定量构效关系(3D-QSAR)和分子对接模型。结合两个模型实验结果,分析化合物的结构与其生物活性间关系。方法采用比较分子分析法(CoMFA)和比较分子相似性指数分析法(CoMSIA)来研究咪唑[1,2-b]哒嗪类mTOR抑制剂的三维定量构效关系,用分子对接方法来研究化合物与受体蛋白之间的相互作用模式。结果:建立了可靠、合理的咪唑[1,2-b]哒嗪类mTOR抑制剂CoMFA(q^(2)=0.628,r^(2)=0.989,r^(2)p red=0.991)和CoMSIA(q^(2)=0.593,r^(2)=0.988,r^(2) pred=0.989)模型。通过分析分子对接模型得出化合物与受体蛋白之间有关键的氢键连接。设计出了新化合物并预测了活性。结论:根据3D-QSAR模型得到咪唑[1,2-b]哒嗪类mTOR抑制剂的结构与生物活性之间的关系,分析分子对接模型发现化合物与受体蛋白之间的作用关系,基于以上设计出了具有较好活性的新化合物。实验的研究发现为该类mTOR抑制剂的设计优化提供了思路。Objective:Toestablish 3D-QSAR models and molecular docking model of imidazo[1,2-b]pyridazinederivatives as mTOR inhibitors.The relationship between structure and activity was analyzed based on the experimental results of the two models.Methods:3D-QSAR of imidazo[1,2-b]pyridazinederivatives as mTOR inhibitors were investigated with Comparative molecular field analusis(CoMFA)and Comparative molecular similarity index analysis(CoMSIA),and molecular docking method was used to study the interaction pattern between the compound and the receptor protein.Results:Reliable and reasonable models of imidazo[1,2-b]pyridazinederivatives as mTOR inhibitors were established(CoMFA:q^(2)=0.628,r^(2)=0.989,r^(2)_(pred)=0.991 and CoMSIA:q^(2)=0.593,r^(2)=0.988,r^(2)_(pred)=0.989).And the key hydrogen bond between the compound and the receptor protein was obtained by analyzing the molecular docking model.New compounds were designed and their activity values were predicted.Conclution:The relationship between the structure and biological activity of imidazo[1,2-b]pyridazinederivatives as mTOR inhibitors is obtained according to the 3D-QSAR models,and the interaction between the compound and the receptor protein is found by analyzing the molecular docking model.Based on the above,new compounds with good activity are designed.The findings of this study provid possible ways to optimize the design of this kind of mTOR inhibitors.

关 键 词：咪唑[1 2-b]哒嗪 MTOR抑制剂 三维定量构效关系 分子对接 

分 类 号：R914[医药卫生—药物化学]