计算机辅助抗丙型肝炎病毒的新型化合物结构设计研究

发布时间：2018-10-25 17:54

【摘要】：目的:丙型肝炎是由丙型肝炎病毒感染引起的病毒性传染病,危害较大,治疗困难,目前尚无有效疫苗进行预防,是世界主要卫生问题之一。本论文对一系列具有抗丙型肝炎病毒活性的化合物进行了研究,旨在构建高效的计算模型,为设计和筛选具有抗丙型肝炎病毒活性的新型化合物结构提供指导。方法:本论文运用计算机辅助药物设计方法对两类具有抗丙型肝炎病毒活性的化合物结构进行了相关研究。首先采用三维定量构效关系方法构建计算模型,分析影响化合物活性的重要结构特征,再运用分子对接方法对化合物在活性位点部位的优势构象进行分析,初步探讨作用机理。在此基础上,设计和筛选具有抗丙型肝炎病毒活性的新型化合物结构。最后,利用计算软件OSIRIS Property Explorer对具有较高活性的化合物进行毒性及类药性等评价。结果:1、用三维定量构效关系方法对42个4-羟氨基α-吡喃酮甲酰胺类似物进行了研究,建立了可靠性和预测能力较高的QSAR模型(q~2=0.569,r~2=0.904,F值为20.756,SEE=0.135,R_(ext)~2=0.653,r_(boot)~2=0.955,SEE_(boot)=0.091,R_p~2=0.609,R_(m(overall))~2=0.680)。通过等势图分析了影响抑制剂活性的结构特征,在此基础上设计并筛选了103个具有抗丙型肝炎病毒活性的新型化合物结构,同时对化合物的活性进行了预测。此外,利用计算软件OSIRIS Property Explorer对40个活性较高的化合物结构进行了毒性及类药性等评价。通过综合分析,2578号化合物为最优结构。2、基于三维定量构效关系和分子对接方法对48个HCV NS5B聚合酶抑制剂进行了研究。基于化合物结构和活性构建了QSAR模型,并对最优模型进行了验证(q~2=0.627,r~2=0.943,F值为86.182,SEE=0.221,R_(ext)~2=0.629,r_(boot)~2=0.975,SEE_(boot)=0.141,R_p~2=0.697,R_(m(overall))~2=0.835),结果说明该模型具有可靠性和较高的预测能力。通过等势图和分子对接结果对影响抑制剂活性的结构特征进行分析,设计并筛选了136个具有抗丙型肝炎病毒活性的新型化合物结构,同时对这些化合物的活性进行预测。通过计算软件OSIRIS Property Explorer对具有较高抑制活性的43个化合物结构进行了毒理性质及类药性等评价。通过综合分析,130号化合物为最优结构。结论:本论文中,三维定量构效关系和分子对接等计算机辅助药物设计方法的结合应用,可对两类具有抗丙型肝炎病毒活性的化合物进行较为系统的研究。通过分析影响化合物抑制活性的结构特征,为设计具有抗丙型肝炎病毒活性的新型化合物结构提供了一定的指导,为丙型肝炎药物的研发和筛选提供了理论依据和新的思路。
[Abstract]:Objective: hepatitis C is a viral infectious disease caused by hepatitis C virus infection, which is harmful and difficult to treat. At present, there is no effective vaccine to prevent hepatitis C, which is one of the major health problems in the world. In this paper, a series of compounds with anti-HCV activity were studied in order to construct an efficient computational model and provide guidance for the design and screening of novel compounds with anti-HCV activity. Methods: the structures of two kinds of compounds with anti-HCV activity were studied by computer-aided drug design. Firstly, a three-dimensional quantitative structure-activity relationship method was used to construct a computational model to analyze the important structural characteristics affecting the activity of the compounds. Then, the molecular docking method was used to analyze the dominant conformation of the compounds at the active sites, and the mechanism of action was preliminarily discussed. On this basis, a novel compound structure with anti-HCV activity was designed and screened. Finally, OSIRIS Property Explorer was used to evaluate the toxicity and drug-like properties of the compounds with high activity. Results: 1. 42 4-hydroxyamino 伪 -pyrroanone formamide analogues were studied by three-dimensional quantitative structure-activity relationship. QSAR models with high reliability and predictive ability were established. The QSAR model was established (the F value of QU2H2A0. 569NV 0.904F was 20.756Se ~ 0.135R _ (ext) ~ 20.653r- (boot) ~ 20.955SEE _ (boot) = 0.091Rpp2O0.609R _ (m (overall) ~ 20.680). The results showed that: (1) the quantitative structure-activity relationship was used to study 42 4-hydroxyamino 伪 -pyranone formamide analogues, and the QSAR model was established with high reliability and predictive ability. Based on the analysis of the structural characteristics of the inhibitors, 103 novel compounds with anti-HCV activity were designed and screened, and the activity of the compounds was predicted. In addition, the toxicity and drug-like properties of 40 compounds with high activity were evaluated by OSIRIS Property Explorer. Based on the quantitative structure-activity relationship and molecular docking method, 48 HCV NS5B polymerase inhibitors were studied. The QSAR model was constructed based on the structure and activity of the compound, and the optimal model was verified (the value of Q _ 2O _ (0.627) ~ (?) ~ (0.943) F is 86.182 QSAR ~ (0.221) (ext) ~ (2). The result shows that the model is reliable and has high predictive ability. The results show that the model is reliable and has a high predictive ability. The results show that the model is reliable and has high predictive ability. Based on the isopotential diagram and molecular docking results, 136 novel compounds with anti-HCV activity were designed and screened, and the activity of these compounds was predicted. The toxicological properties and drug-like properties of 43 compounds with high inhibitory activity were evaluated by computer software OSIRIS Property Explorer. The optimum structure of compound 130 was found by comprehensive analysis. Conclusion: in this paper, the combination of three-dimensional quantitative structure-activity relationship and molecular docking can be used to study two kinds of compounds with anti-HCV activity. By analyzing the structural characteristics of the inhibitory activity of the compounds, it provides some guidance for the design of new compounds with anti-hepatitis C virus activity, and provides a theoretical basis and a new way of thinking for the development and screening of hepatitis C drugs.
【学位授予单位】：青岛大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R91

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