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研究生:盧建勝
研究生(外文):Chien-Sheng Lu
論文名稱: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
論文名稱(外文):Study on Generation of Chemical Function Based Pharmacophore Models for Hepatitis C virus NS3 Protease Inhibitors
指導教授:林志侯
學位類別:碩士
校院名稱:國立清華大學
系所名稱:分子醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:42
中文關鍵詞:C型肝炎病毒藥效基團CATALYST軟體
外文關鍵詞:HCVPHARMACOPHORECATALYST PROGRAM
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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 this study as a 3D query tool in virtual screening to retrieve new chemical entities as potent HCV NS3 inhibitors.
中文摘要.........................Ⅰ
英文摘要.........................Ⅱ
誌謝辭..........................Ⅲ
圖目錄..........................Ⅳ
表目錄..........................Ⅴ

第一章 緒論
1.1 C型肝炎病毒簡介 ...................1
1.2 Catalyst軟體簡介...................6
1.3 研究動機與目的....................11

第二章 材料與方法
2.1 使用材料.......................13
2.2 操作方法
2.2.1 Catalyst操作方法 ................17
2.2.2 GOLD操作方法 ..................19

第三章 結果與討論
3.1 訓練組的確認.....................21
3.2 測試組的確認.....................24
3.3 預測主結構不同的分子之活性..............26
3.4利用GOLD得到之構形來產生藥效基團..........27

第四章 結論與未來展望.................34

第五章 參考文獻與附錄.................35
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