【摘要】：目的:丙型肝炎是由丙型肝炎病毒感染引起的病毒性傳染病,危害較大,治療困難,目前尚無有效疫苗進行預(yù)防,是世界主要衛(wèi)生問題之一。本論文對一系列具有抗丙型肝炎病毒活性的化合物進行了研究,旨在構(gòu)建高效的計算模型,為設(shè)計和篩選具有抗丙型肝炎病毒活性的新型化合物結(jié)構(gòu)提供指導(dǎo)。方法:本論文運用計算機輔助藥物設(shè)計方法對兩類具有抗丙型肝炎病毒活性的化合物結(jié)構(gòu)進行了相關(guān)研究。首先采用三維定量構(gòu)效關(guān)系方法構(gòu)建計算模型,分析影響化合物活性的重要結(jié)構(gòu)特征,再運用分子對接方法對化合物在活性位點部位的優(yōu)勢構(gòu)象進行分析,初步探討作用機理。在此基礎(chǔ)上,設(shè)計和篩選具有抗丙型肝炎病毒活性的新型化合物結(jié)構(gòu)。最后,利用計算軟件OSIRIS Property Explorer對具有較高活性的化合物進行毒性及類藥性等評價。結(jié)果:1、用三維定量構(gòu)效關(guān)系方法對42個4-羥氨基α-吡喃酮甲酰胺類似物進行了研究,建立了可靠性和預(yù)測能力較高的QSAR模型(q~2=0.569,r~2=0.904,F值為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)。通過等勢圖分析了影響抑制劑活性的結(jié)構(gòu)特征,在此基礎(chǔ)上設(shè)計并篩選了103個具有抗丙型肝炎病毒活性的新型化合物結(jié)構(gòu),同時對化合物的活性進行了預(yù)測。此外,利用計算軟件OSIRIS Property Explorer對40個活性較高的化合物結(jié)構(gòu)進行了毒性及類藥性等評價。通過綜合分析,2578號化合物為最優(yōu)結(jié)構(gòu)。2、基于三維定量構(gòu)效關(guān)系和分子對接方法對48個HCV NS5B聚合酶抑制劑進行了研究�；诨衔锝Y(jié)構(gòu)和活性構(gòu)建了QSAR模型,并對最優(yōu)模型進行了驗證(q~2=0.627,r~2=0.943,F值為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),結(jié)果說明該模型具有可靠性和較高的預(yù)測能力。通過等勢圖和分子對接結(jié)果對影響抑制劑活性的結(jié)構(gòu)特征進行分析,設(shè)計并篩選了136個具有抗丙型肝炎病毒活性的新型化合物結(jié)構(gòu),同時對這些化合物的活性進行預(yù)測。通過計算軟件OSIRIS Property Explorer對具有較高抑制活性的43個化合物結(jié)構(gòu)進行了毒理性質(zhì)及類藥性等評價。通過綜合分析,130號化合物為最優(yōu)結(jié)構(gòu)。結(jié)論:本論文中,三維定量構(gòu)效關(guān)系和分子對接等計算機輔助藥物設(shè)計方法的結(jié)合應(yīng)用,可對兩類具有抗丙型肝炎病毒活性的化合物進行較為系統(tǒng)的研究。通過分析影響化合物抑制活性的結(jié)構(gòu)特征,為設(shè)計具有抗丙型肝炎病毒活性的新型化合物結(jié)構(gòu)提供了一定的指導(dǎo),為丙型肝炎藥物的研發(fā)和篩選提供了理論依據(jù)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 偽 -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 偽 -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.
【學(xué)位授予單位】：青島大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R91

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