摘要：癌症是人们谈之色变的疾病，人类对于治疗各种癌症的探索也从未停止过。PI3K/Akt/mTOR是重要的信号转导通路，在肿瘤细胞中被激活。 mTORC1和mTORC2的双重抑制剂可通过抑制异常信号通路抑制肿瘤生长和血管生成。为深入了解尿素吗啉类似物作为mTOR抑制剂的结构活性关系，通过分子建模研究包括三维定量结构活性（3D-QSAR）和分子对接。使用由3D-QSAR创建的CoMFA CoMSIA和Topomer CoMFA方法来建立稳定模型，并得到双重抑制剂的显著相关系数（对于CoMFA模型，q2=0.750，r2=0.931；对于CoMSIA模型，q2=0.745，r2=0.927；对于Topomer CoMFA模型，q2=0.780，r2=0.950）。同时，使用测试集合（CoMFA的外部预测相关系数rpred2=0.696；CoMSIA的rpred2=0.794）验证所生成的模型。这些相关系数证实这些模型是正确的，并且可以用于预测新化合物。之后，进行分子对接研究以研究这些类似物与受体蛋白之间的分子相互作用。在该研究中，所选择的尿素吗啉类化合物停靠在活性位点。确定一些关键氨基酸残基如Lys802，Ser806，Lys808，Val882。这项研究令人满意的结果可能有助于研究，并可用于设计新的双重抑制剂。70045

毕业论文关键词： mTOR；3D-QSAR；Topomer CoMFA；分子对接模拟

Molecular Design and Process Amplification Design of urea-morpholine mTOR Inhibitors

Abstract: Cancer is a disease that people afraid to talk about, and human exploration for the treatment of various cancers has never stopped..PI3K/Akt/mTOR was important signal transduction pathway, activated in tumor cells. The dual inhibitors of mTORC1 and mTORC2 could suppress the tumor growth and angiogenesis by inhibiting the abnormal signal pathway. To deeply understand the structure-activity relationship of urea-morpholine analogues as inhibitors of mTOR, molecular modeling studies include three-dimensional quantitative structure activity (3D-QSAR) and molecular docking were carried out. CoMFA CoMSIA and Topomer CoMFA methods created by 3D-QSAR were used to building stable model, and significant correlation coefficients for dual inhibitors (q2 = 0.750, r2 = 0.931 for CoMFA model; q2 = 0.745, r2 = 0.927 for CoMSIA model; q2 = 0.780, r2 = 0.950 for Topomer CoMFA model) were obtained. At the same time, the generated models were validated using the test sets (external predictive correlation coefficient rpred2 = 0.696 for CoMFA; rpred2 = 0.794 for CoMSIA). These correlation coefficients confirmed that these models were correct and could be used to predict new compounds. Afterward, molecular docking study was performed to study the molecular interactions between these analogues and the receptor protein. In this study, the selected urea-morpholine compounds were docking into the active site. Some key amino acid residues such as Lys802, Ser806, Lys808, Val882 were determined. The satisfactory results from this study may aid in the research and can be used to design novel dual inhibitors.

Keywords: mTOR, 3D-QSAR, Topomer CoMFA; Molecular docking simulations

目  录

1  绪论 1

1.1  mTOR的简介 1

1.1.1  mTOR的概念 1

1.1.2  mTOR的信号通路 1

1.1.3  mTOR与肿瘤 2

1.2  mTOR抑制剂概述 3

1.2.1  雷帕霉素 3

1.2.2  替西罗莫司 3

1.2.3  依维莫司 4

1.2.4  NVP-BEZ235 4

1.3  计算机辅助药物设计方法概述 4

1.3.1  计算机辅助药物设计简介