受体蛋白酪氨酸激酶血管内皮生长因子受体-2抑制剂的设计
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摘要
血管新生是许多生理和病理进程发生的重要机理。在生物体内,血管新生需经过多步精细调控历程,现有研究表明血管内皮生长因子(VEGF)及其受体蛋白酪氨酸激酶,尤其是血管内皮生长因子受体-2(VEGFR-2)所介导的信号级联通路是其中关键性的调节途径。VEGF/VEGFR-2所介导的信号级联通路可以调控血管内皮细胞的增殖、迁移、存活和通透性的改变,促进血管的新生。研发VEGFR-2抑制剂分子以达到阻碍血管新生的疗效,已经成为了现代治疗肿瘤等疾病的重要策略。
本文采用计算机辅助药物设计的方法研究了新型的苯并咪唑类血管内皮生长因子受体-2抑制剂的活性与结构之间的关系,并且提出了化合物的药效团模型和提高化合物抑制活性的结构改造信息。作为VEGFR-2抑制剂的药物研发的前期工作,本课题可以为后续的研究提供一个良好的平台。本文的主要内容包括以下四个方面的:
第一部分是绪论。介绍了血管内皮生长因子受体所介导的信号通路及其抑制剂的研究进展,此外还概述了计算机辅助药物设计的相关理念。
第二部分是药效团模型的构建。使用距离比较法建立苯并咪唑类抑制剂分子的药效团模型,随后对于得分最高的药效团模型进行了优化和验证。
第三部分是定量构效关系研究。对苯并咪唑类抑制剂分子使用CoMFA和CoMSIA方法进行了三维定量构效关系研究,并得到了良好预测能力的模型,为抑制剂的改进提供了理论依据。
第四部分是对新型抑制剂的设计的概述,提出了新型的1,8-二氮萘类VEGFR-2类的抑制剂分子的设想。
Angiogenesis is of great importance to a variety of normal physiological processes and pathological disorders. It is tightly regulated by many mechanisms, among which vascular endothelial growth factor (VEGF) is one of the most potent promoters. VEGF binds and activates its specific receptor tyrosine kinases, especially vascular endothelial growth factor receptor-2(VEGFR-2). VEGFR-2 mediates the key functional and biochemical effects of VEGF in endothelial cells including proliferation, migration, survival, and permeability. Research and development of VEGFR-2 inhibitors in order to prohibit angiogenesis has become a significant strategy for cancer therapy, as well as other diseases treatment.
Computer aided drug design method was used to research the structure-activity relationship of benzimidazole derivatives, which were novel VEGFR-2 inhibitors. As a result, pharmacophore models were established, the informations concerning how to improve the inhibiting activity were also obtained. As a preparatory work for research and development of VEGFR-2 inhibitors, this research will provide a good foundation for the subsequent research. This paper includes four parts:
Part one, introduction. VEGF/VEGFR-2 signaling pathway mechanisms and VEGFR-2 inhibitors research progress were introduced in brief. The theory of computer aided drug design was also summarized.
Part two, benzimidazole derivatives were researched to establish pharmacophore models. A distance comparison method was used as the arithmetic. The pharmacophore model, which with the highest score, was refined and validated later.
Part three, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used to do three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis of benzimidazole derivatives. CoMFA and CoMSIA models were builded and validated. With good predicted ability, those models could be useful for improving this kind of inhibitors.
Part four, as a assume, 1,8-naphthyridine derivatives were design as novel VEGFR-2 inhibitors.
本文采用计算机辅助药物设计的方法研究了新型的苯并咪唑类血管内皮生长因子受体-2抑制剂的活性与结构之间的关系,并且提出了化合物的药效团模型和提高化合物抑制活性的结构改造信息。作为VEGFR-2抑制剂的药物研发的前期工作,本课题可以为后续的研究提供一个良好的平台。本文的主要内容包括以下四个方面的:
第一部分是绪论。介绍了血管内皮生长因子受体所介导的信号通路及其抑制剂的研究进展,此外还概述了计算机辅助药物设计的相关理念。
第二部分是药效团模型的构建。使用距离比较法建立苯并咪唑类抑制剂分子的药效团模型,随后对于得分最高的药效团模型进行了优化和验证。
第三部分是定量构效关系研究。对苯并咪唑类抑制剂分子使用CoMFA和CoMSIA方法进行了三维定量构效关系研究,并得到了良好预测能力的模型,为抑制剂的改进提供了理论依据。
第四部分是对新型抑制剂的设计的概述,提出了新型的1,8-二氮萘类VEGFR-2类的抑制剂分子的设想。
Angiogenesis is of great importance to a variety of normal physiological processes and pathological disorders. It is tightly regulated by many mechanisms, among which vascular endothelial growth factor (VEGF) is one of the most potent promoters. VEGF binds and activates its specific receptor tyrosine kinases, especially vascular endothelial growth factor receptor-2(VEGFR-2). VEGFR-2 mediates the key functional and biochemical effects of VEGF in endothelial cells including proliferation, migration, survival, and permeability. Research and development of VEGFR-2 inhibitors in order to prohibit angiogenesis has become a significant strategy for cancer therapy, as well as other diseases treatment.
Computer aided drug design method was used to research the structure-activity relationship of benzimidazole derivatives, which were novel VEGFR-2 inhibitors. As a result, pharmacophore models were established, the informations concerning how to improve the inhibiting activity were also obtained. As a preparatory work for research and development of VEGFR-2 inhibitors, this research will provide a good foundation for the subsequent research. This paper includes four parts:
Part one, introduction. VEGF/VEGFR-2 signaling pathway mechanisms and VEGFR-2 inhibitors research progress were introduced in brief. The theory of computer aided drug design was also summarized.
Part two, benzimidazole derivatives were researched to establish pharmacophore models. A distance comparison method was used as the arithmetic. The pharmacophore model, which with the highest score, was refined and validated later.
Part three, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used to do three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis of benzimidazole derivatives. CoMFA and CoMSIA models were builded and validated. With good predicted ability, those models could be useful for improving this kind of inhibitors.
Part four, as a assume, 1,8-naphthyridine derivatives were design as novel VEGFR-2 inhibitors.
引文
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