核苷酸氧化损伤修复酶MTH1抑制剂的设计与合成

发布时间：2018-04-30 22:25

本文选题：核苷酸氧化损伤修复酶MTH1 + 全新药物设计　；参考：《青岛科技大学》2017年硕士论文

【摘要】：核苷酸氧化损伤修复酶MTH1通过作用于细胞核苷酸池,防止氧化损伤的嘌呤核苷酸错误的编入核酸分子中,从而间接维护遗传物质的稳定性。研究显示,肿瘤细胞的DNA氧化损伤修复机制存在很多缺陷,而MTH1酶则是维护肿瘤特别是RAS突变型肿瘤DNA分子正确复制及细胞增殖的关键。通过抑制MTH1酶的活性,肿瘤细胞内氧化应激水平会进一步上升,导致更多的DNA损伤从而引起肿瘤细胞增殖的停滞甚至凋亡,以达到肿瘤治疗的目的。因此,核苷酸氧化损伤修复酶MTH1是RAS突变型肿瘤治疗中小分子药物的理想靶点。本文通过采用计算机辅助药物设计方法,基于核苷酸氧化损伤修复酶MTH1的三维结构,及其相关抑制剂的分子结构进行全新药物设计。首先应用碎片生长的方法,设计了683个化合物,接着对这些化合物进行ADME/Tox药理学性质评估及其分子对接的虚拟筛选,选择出10种打分较高的化合物进行进一步的结合模式研究。对体系进行50ns的分子动力学平衡研究,通过考察其动力学稳态并观察其平衡后构象进一步确定了4种结合最佳的分子。然后又基于骨架跃迁和药效团筛选方法,构建并筛选了537个全新分子结构,之后通过各虚拟筛选手段及其动力学模拟方法,最终选定2种最优分子进行下一阶段的研究。为了探索MTH1酶抑制剂的多靶标作用,本文通过使用反向虚拟筛选的方法,对设计并筛选到的化合物进行反向药效团搜索研究。从各分子靶向的前100个药效团中筛选出靶向次数最多的大分子结构,通过进一步分析这些蛋白酶与相应化合物的相互作用模式,研究这些蛋白质分子的生物学作用,以考察这些小分子化合物的多靶标特性及其可能的副作用。本文对化合物12即3-((((5-氨基吡唑并[1,5-c]嘧啶-3-基)甲基)氨基)甲基)苯酚进行了合成研究,通过逆合成路线分析,初步设计了一条简便合成路线,并对中间体5-氨基吡唑并[1,5-c]嘧啶-3-甲醛的合成路线进行了进一步的优化。本文通过使用计算机辅助药物设计方法对核苷酸氧化损伤修复酶MTH1的抑制剂进行了全新设计,并进一步探索了相关化合物的合成,为MTH1相关抑制剂的研发奠定了基础。
[Abstract]:Nucleotide oxidative damage repair enzyme (MTH1) indirectly maintains the stability of genetic material by acting on the cell nucleotide pool to prevent the oxidative damage of purine nucleotides from miscoding into nucleic acid molecules. Studies have shown that there are many defects in the repair mechanism of DNA oxidative damage in tumor cells, and MTH1 enzyme is the key to maintain the correct replication of DNA molecules and cell proliferation of tumor cells, especially RAS mutant tumors. By inhibiting the activity of MTH1 enzyme, the level of oxidative stress in tumor cells will rise further, leading to more DNA damage, thus leading to tumor cell proliferation arrest or even apoptosis, in order to achieve the purpose of tumor therapy. Therefore, nucleotide oxidative damage repair enzyme (MTH1) is an ideal target for small molecular drugs in the treatment of RAS mutant tumors. Based on the three-dimensional structure of nucleotide oxidative damage repair enzyme (MTH1) and the molecular structure of its related inhibitors, a new drug design was carried out by computer aided drug design (CAD). First, 683 compounds were designed by using the method of fragment growth. Then, the pharmacological properties of these compounds were evaluated by ADME/Tox and the virtual screening of molecular docking, and 10 compounds with higher scores were selected to further study the binding mode. The molecular dynamics equilibrium of 50ns system was studied. The four best binding molecules were further determined by investigating the kinetic stability and the conformation after observing the equilibrium. Then, 537 novel molecular structures were constructed and screened based on skeleton transition and pharmacophore screening methods. Then, two kinds of optimal molecules were selected for the next stage by virtual screening methods and kinetic simulation methods. In order to explore the multi-target effect of MTH1 enzyme inhibitors, reverse pharmacophore search was carried out on the designed and screened compounds by using reverse virtual screening method. The macromolecular structures with the largest number of targets were screened from the first 100 pharmacophore targeted by each molecule. The biological effects of these proteins were studied by further analyzing the interaction patterns of these proteases with the corresponding compounds. To investigate the multi-target properties of these small molecular compounds and their possible side effects. In this paper, the synthesis of compound 12 (3-Aminopyrazolido [1AZO5-c] pyrimidine-3-methyl-methyl) phenol was studied. A simple synthetic route was preliminarily designed through the analysis of the inverse synthesis route. The synthesis route of the intermediate 5-aminopyrazolyl [1 5-c] pyrimidine-3-formaldehyde was further optimized. In this paper, the inhibitors of nucleotide oxidative damage repair enzyme (MTH1) were designed by computer aided drug design (CAD), and the synthesis of related compounds was further explored, which laid a foundation for the research and development of MTH1 inhibitors.
【学位授予单位】：青岛科技大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914

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