嘧啶衍生物类PI3K/mTOR双重抑制剂的3D-QSAR及分子对接研究

3D-QSAR and Surflex-dock study of pyrimidine scaffold compounds as dual PI3K/mTOR inhibitors

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.

The PI3K/Akt/mTOR pathway, which impacts cell growth and proliferation, is usual abnormally activated in cancer. Inhibiting both PI3K 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.