激活素受体样激酶抑制剂的三维定量构效关系和分子对接研究

发布时间：2018-10-12 09:04

【摘要】：计算机辅助药物设计(CADD)相较于传统的HTS和组合化学能够更有针对性的搜寻,继而提高新型药物分子的命中率。它不仅能在分子的基础上解释药物的治疗活性,也能预测可改善生物活性的新的衍生物。在药物发现过程中,CADD主要用于三个方面:(1)将大型化合物库过滤成可以进行实验测试的少数活性化合物的集合;(2)指导先导化合物的优化,增加其亲和力或优化药物代谢和药代动力学性质,包括吸收,分布,代谢,排泄和潜在毒性(ADMET);(3)设计新化合物,通过"分子生长法"或"片段拼接法"设计新的化学型态。本论文共分为4章:第一章:分为两个部分,第一部分简单概述了药物发现与分子模拟的基本发展路线;第二部分详细介绍了转化生长因子超家族与激活素受体样激酶的关系,以及它们发挥生物作用的机制。第二章:重点探讨了计算方法学,主要分析了定量构效关系、分子对接以及同源建模的原理及方法学,简单介绍了本课题的研究路线。第三章:采用同源建模方法构建ALK4,ALK7蛋白晶体结构;利用分子对接方法,对比分析了 EW-7197和Galunisertib两个临床在研药物分子分别与ALK5的蛋白晶体相互作用的机制和区别,并将EW-7197与激活素受体样激酶的7个亚型分别进行分子对接,逐一解析其与相应蛋白的相互作用模式和机制,进一步验证其对ALK5的选择性。第四章:采用3D-QSAR和分子对接方法,对与EW-7197具相同母核的一系列咪唑类ALK5抑制剂进行分子对接和3D-QSAR研究。以EW-7197与ALK5对接后的优势构象为模板分子,用61个化合物同时构建CoMFA和CoMSIA模型,分析势能图与分子活性的关系。为设计新型高选择性,高活性,高安全性以及低毒副作用的抑制剂奠定了理论基础,减少了实际筛选的工作量;也为TGF-β/活化素途径抑制剂用于临床治疗赋予了巨大的希望。
[Abstract]:Compared with traditional HTS and combinatorial chemistry, computer-aided drug design (CADD) can search more effectively and improve the hit rate of new drug molecules. It can not only explain the therapeutic activity of drugs on molecular basis, but also predict new derivatives that can improve biological activity. In the process of drug discovery, CADD is mainly used in three aspects: (1) filtering a large compound library into a collection of a few active compounds that can be tested experimentally; (2) guiding the optimization of leading compounds. New compounds were designed by increasing their affinity or optimizing their metabolic and pharmacokinetic properties, including absorption, distribution, metabolism, excretion and potentially toxic (ADMET); (_ 3. New chemical patterns were designed by "molecular growth" or "fragment splicing". This thesis is divided into four chapters: chapter one: it is divided into two parts. The first part briefly summarizes the basic development route of drug discovery and molecular simulation, the second part introduces the relationship between the superfamily of transforming growth factor and activin receptor-like kinase in detail. And their biological mechanisms. The second chapter mainly discusses the computational methodology, mainly analyzes the principle and methodology of quantitative structure-activity relationship, molecular docking and homologous modeling, and briefly introduces the research route of this subject. In chapter 3, the crystal structure of ALK4,ALK7 protein was constructed by homologous modeling, and the mechanism and difference of the interaction between EW-7197 and Galunisertib were analyzed by molecular docking method. The seven subtypes of EW-7197 and activin receptor-like kinase were linked to each other, and the interaction patterns and mechanisms with the corresponding proteins were analyzed one by one to further verify their selectivity to ALK5. Chapter 4: using 3D-QSAR and molecular docking method, a series of imidazole ALK5 inhibitors with the same mother nucleus as EW-7197 were studied by molecular docking and 3D-QSAR. Using the dominant conformation of EW-7197 and ALK5 as template molecule, 61 compounds were used to construct CoMFA and CoMSIA models at the same time, and the relationship between potential energy diagram and molecular activity was analyzed. It lays a theoretical foundation for the design of new inhibitors with high selectivity, high activity, high safety and low toxicity and side effects, reduces the workload of practical screening, and gives great hope for the application of TGF- 尾 / activin pathway inhibitors in clinical treatment.
【学位授予单位】：广州中医药大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R91

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