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摘要：疟疾是世界许多地区的一个主要杀手。 咪唑哒嗪衍生物是一系列芳香杂环化合物，具有杀虫、杀菌、调节植物生长、抗病毒、抗惊厥、抗癌等高度的生物活性，此外还能作为有机液晶因为其具有良好的介晶性。经研究表明可作为抗疟疾标靶PfCDPK1抑制剂的分子。本文主要使用了比较分子力场分析方（CoMFA）和比较分子相似性指数分析法（CoMSIA），对一系列新型咪唑哒嗪类似物的结构参数和从文献上得到的pIC50值进行分析，以102个总分子数量中的90个分子的结构和pIC50值作为训练集。并且使用三文定量构效关系（3D-QSAR）方法建立模型和采用抽一法(leave one out，LOO) 得到交叉验证系数q2与相关系数R2的值来检测模型的可靠性，之后选出18个线性不好的咪唑哒嗪类似物组成测试集，依此来验证模型的预测能力。通过从CoMFA、CoMSIA等势图的结果进行分析，根据色块图设计新的抑制活性更高的化合物。实验结果证明本文所建立的3D-QSAR模型具有明确、良好的预测能力。此外还通过分子对接的方法，计算配体与受体结合的模式和亲和力，并对新分子结果进行打分，评判结合程度。并且本文基于一系列已知化学结构的咪唑哒嗪类似物，构建了其三文药效团模型。挑选出构效关系最好的药效团模型，通过虚拟筛选的方式找出配体与受体蛋白相结合的部分氨基酸。34260
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毕业论文关键词： 三文定量构效关系（3D-QSAR）；新型咪唑哒嗪类似物；pIC50值；CoMFA；CoMSIA
Study on the molecular design of anti malaria target PfCDPK1 as inhibitors of imidazole pyridazine analogues
Abstract：Malaria is a major killer in many parts of the world. Imidazole pyridazine derivatives are a series of aromatic heterocyclic compounds, with insecticidal, sterilization, regulating plant growth, antivirus, anticonvulsants, anti-cancer, such as high biological activity, and also can be used as organic liquid crystal because of its good structure. Studies show that the target can be used as antimalarial PfCDPK1 inhibitor molecules. This article mainly USES the comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA), for a series of novel imidazole pyridazine analogue structure parameters and pIC50 values from the literature were analyzed, and in 102 the total number of 90 molecules structure and pIC50 value as the training set. And using three-dimensional quantitative structure-activity relationship (3 d - QSAR) method to establish model and use smoke a method (leave one out, LOO) gain coefficient of cross-validation q2 and correlation coefficient R2 values to the reliability of the test model, then select 18 linear bad imidazole pyridazine analogue test set of validation according to the predictive ability of the model. Through from CoMFA, CoMSIA equipotential chart the results of the analysis, according to the color piece figure design new higher inhibitory activity of compounds. Experimental results prove the established 3 d - QSAR model is clear and good prediction ability. Also, by using the method of molecular docking computation model and the affinity ligand and receptor, and the result of the new molecular scores, judge bonding degree. And this article is based on a series of known chemical structures of imidazole pyridazine analogues, build the 3 d pharmacophore model. Pick out the structure-activity relationship of the best pharmacophore model, find out by means of virtual screening combined part of ligand and receptor protein amino acids.
Key Words：Three-dimensional quantitative structure-activity relationship (3D-QSAR)；new Imidazole pyridazine analogues ；pIC50 value；CoMFA；CoMSIA
目录
第一章 1
1.1 研究的背景与目的 1
1.2 研究现状和进展 3
1.3 主要研究内容 5