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對C型肝炎病毒NS3蛋白酶抑制劑產生化學作用力為主的藥效基團之研究 ; Study on Generation of Chemical Function Based Pharmacophore Models for Hepatitis C virus NS3 Protease Inhibitors

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العنوان: 對C型肝炎病毒NS3蛋白酶抑制劑產生化學作用力為主的藥效基團之研究 ; Study on Generation of Chemical Function Based Pharmacophore Models for Hepatitis C virus NS3 Protease Inhibitors
المؤلفون: 盧建勝, Chien-Sheng Lu
المساهمون: 林志侯教授
سنة النشر: 2004
المجموعة: National Tsing Hua University Institutional Repository (NTHUR)
مصطلحات موضوعية: C型肝炎病毒, 藥效基團, CATALYST軟體, HCV, PHARMACOPHORE, CATALYST PROGRAM
الوقت: 37
الوصف: 碩士 ; 國立清華大學 ; 分子醫學研究所 ; GH000914282 ; 以一系列pyrimidinone與pyrazinone為主結構的C型肝炎病毒NS3蛋白酶抑制劑來產生化學作用力為主的藥效基團，這個藥效基團是利用一組20個抑制劑的訓練組所產生。它的活性值是IC50，從20到30000 nM。最具預測能力的藥效基團(hypothesis 1)由三種作用力所組成，有兩個疏水性作用力，一個氫鍵提供者，一個疏水性芳香作用力，它的相關係數為0.943，均方根平方值為0.886，null cost與fixed cost的差值為52.33 bits，null cost與total cost的差值為42.81 bits。這個藥效基團經由catScramble亂數重排交叉確認，得到的結果確定由訓練組所產生的藥效基團不是因為機會而得到的。最好的藥效基團(hypothesis1)再用30個抑制劑的測試組來驗證。在分辨活性與不活性的分子時還算蠻正確的，有76.67%的成功率。接下來用兩家藥廠的兩個結構多樣之HCV NS3蛋白酶抑制劑與藥效基團作疊合，一個預測成高活性另一個預測成無活性，也許是這兩個化合物作用的機制不同。這些多重確認的方法提供了在使用這個藥效基團在虛擬篩選中當作三度空間搜尋工具，增加找到可能之C型肝炎病毒新抑制劑的信心。 ; Chmical function based pharmacophore models were developed for a series of pyrimidinone- and pyrazinone-based HCV NS3 protease inhibitors. The pharmacophore models were generated using a training set consisting of 20 inhibitors. The activity spread, expressed in IC50 of training set molecules was from 20 to 30000 nM. The most predictive pharmacophore model (hypothesis 1), consisting of three features, namely, two hydrophobic, one hydrogen bond donor and one hydrophobic aromatic, had a correlation (r) of 0.943 and a root mean square of 0.886, and the cost difference between null cost and fixed cost was 52.33 bits and the cost difference between null cost and total cost was 42.81 bits. The model was cross validated by randomizing the data using the CatScramble technique. The results confirmed that the pharmacophore models generated from the training set were not due to chance correlation. The best model (hypothesis 1) was validated using test set molecules (total of 30) and performed not bad in classifying active and inactive molecules, it is 76.67% success. The model was further validated by mapping onto it a diverse set of two HCV NS3 protease inhibitor identified by two different pharmaceutical companies. The best model predicted one compounds as being highly active and one inactive, maybe these two compounds work by different mechanism. These multiple validation approaches provide confidence in the utility of this pharmacophore model developed in ...
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الإتاحة: http://nthur.lib.nthu.edu.tw/dspace/handle/987654321/28613Test
رقم الانضمام: edsbas.D83BE2C2
قاعدة البيانات: BASE
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