【摘要】 PI3K/Akt/mTOR信号通路在癌细胞的生长和增殖中异常激活,对PI3K和mTOR位点的抑制可有效阻断信号通路的传导,是药物设计的理想靶点.本文选择38个嘧啶类小分子抑制剂进行3D-QSAR和分子对接研究.采用比较分子力场分析(CoMFA)和比较分子相似性指数分析(CoMSIA)方法,建立了三维定量构效关系模型,结果表明,该模型具有良好的稳定性和预测能力,可运用分子对接研究小分子抑制剂与PI3K和mTOR蛋白受体的作用模式.通过对QSAR模型的三维等势图以及受体与配体的相互作用模式分析后,优化出10个小分子化合物并预测其活性,发现一些小分子化合物活性提高,这为PI3K/mTOR双重抑制剂的设计筛选提供了借鉴.更多还原

【Abstract】 The PI3K/Akt/mTOR pathway,which impacts cell growth and proliferation,is usual abnormally activated in cancer.Inhibiting both PI3 K and mTOR can switch off this pathway,which is an ideal target for drug design.In this article,3D-QSAR and Surflex-dock were carried out to study a series of 38 pyrimidine derivatives as dual PI3K/mTOR inhibitors.The comparative molecular field analysis(CoMFA) and comparative molecular similarity indices analysis(CoMSIA) were used to establish 3D-QSAR model,and the results showed that the model has a good stability and predictability.The study of interaction between small molecule inhibitors and PI3K/mTOR proteins receptor was based on the Surflex-dock.According to the contour maps and molecular docking results,ten derivatives were designed and predicted,and modified compounds have a better activity.These data provide a reference for designing and screening new dual PI3K/mTOR inhibitors.更多还原