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研究生： 王文宏
論文名稱： Celebrex衍生物—PDK1抑制劑—的三維定量構效關係研究
指導教授： 孫英傑
學位類別： 碩士
Master
系所名稱： 化學系
Department of Chemistry
論文出版年： 2006
畢業學年度： 94
語文別： 中文
論文頁數： 50
中文關鍵詞： Celebrex 、PDK1抑制劑 、三維定量構效關係
論文種類： 學術論文
相關次數： 點閱：259  下載：0 
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    • 本論文中以celebrex為基礎的PDK1抑制劑進行比較分
    子場分析法(CoMFA)之三維定量構效關係(3D-QSAR)研究。
    使用Gaussian98套裝軟體進行量子化學計算以獲得化合物的
    結構。將這些化合物分群進行CoMFA計算得到相關數值q2介
    於0和0.8之間。其中有些q2值較低可能主要是由於生物活性
    範圍選擇不夠廣所造成。在化合物個數介於11到16之間的幾
    組計算中得到的q2值介於0.5和0.8。高q2值的計算結果可提供
    這些化合物進行化學修飾的方向以增進其生物活性，並且對
    未來以celebrex為基礎的抗癌藥物設計有所幫助。

    總目錄 圖目錄 III 表目錄-----------------------------------------------V 中文摘要---------------------------------------------VI 英文摘要---------------------------------------------VII 目錄 Celebrex衍生物—PDK1抑制劑—的三維定量構效關係研究 第一章、緒論----------------------------------------1 1-1 前言-------------------------------------------2 1-2 研究動機----------------------------------------3 1-3 PI3K/Akt信號通路(signaling pathway)與癌細胞、腫瘤的關係--6 1-4 非類固醇抗炎藥物(Non-steroidal Anti-inflammatory Drugs, NSAIDs)--------------------------------------------8 1-5 三維定量構效關係(3D-Quantitative Structure-Activity Relationship, 3D-QSAR)----------10 1-6 研究目標----------------------------------------12 第二章、理論及方法-----------------------------------13 2-1 參數法3(Parametric Method 3, PM3)--------------14 2-2 分子之穩定結構計算-------------------------------16 2-3 .Tripos力場能量最小化(Tripos Force Field Minimization)--------------------------------------17 2-4 比較分子場分析(Comparative Molecular Field Analysis, CoMFA)-----------------------------------19 2-4.1 分子排列(Molecular Alignment, Superimpose) ---------------------------------------------21 2-4.2 晶格(Lattice)--------------------------------22 2-4.3 部分最小平方法(Partial Least Square, PLS)--23 2-4.4 交叉驗證(Cross-validation)----------------------24 第三章、計算結果與討論--------------------------------26 3-1 計算所得之化合物結構---------------------------------27 3-2 .CoMFA計算的結果：q2與IC50值及討論---------------29 3-3 空間與靜電分佈圖(Steric and Electrostatic Contour Map)--------------------------------------------41 第四章、結論-------------------------------------46 第五章、參考文獻---------------------------------48 圖目錄 圖1-2 ATP與PDK1形成氫建---------------------------------3 圖1-3 PI3K-Akt的信號通路調控模型------------------------6 圖2-4 比較分子場分析程序---------------------------------20 圖2-2.3 交叉驗證法程序------------------------------------25 圖3-1.1 化合物35兩雙面角雙重掃描之後相對能量圖---------------27 圖3-1.2 化合物35經PM3結構最佳化後的結構-----------------28 圖3-2.1 PM3最佳化的結構，使用在CoMFA計算得到最好q2值----30 圖3-2.2 (a)37個化合物分子相同部分的結構圖(b)11個分子 (0~6,20,23,34~35)的空間重疊圖-----------------------31 圖3-2.3 預測IC50值(Calculated IC50)與實際IC50(Experimental IC50)的相關圖-------------------------------------32 圖3-2.4 G-A在不同位置重疊(PM3結構,M3 Mulliken電荷)--------34 圖3-2.5 化合物0~24在不同位置重疊(PM3結構,M3 Mulliken電荷) --------------------------------35 圖3-2.6 依據取代官能基分為三群：G-1A(0~6,20)、G-1B(9~19)和 G-1C(7~8,21~24)----------------------------------37 圖3-2.7 不同分子個數的空間與靜電分佈圖(PM3結構,PM3 Mulliken電荷)---------------------------------39 圖3-2.8 化合物22、23和24的PM3結構重疊---------------40 圖3-3 11個化合物(0~6,20,23,34~35)CoMFA的空間與靜電分佈圖----41 表目錄 表1-2 Celebrex及其36個衍生物對PDK1或PC-3細胞系的抑制活性-----4 表3-2.1 11個化合物(0~6,20,23,34~35)的CoMFA結果---------32 表3-2.2 預測(計算)IC50值與實際(觀察)IC50值-------------33 表3-3.1 化合物0~24的結構與PDK1 IC50值-------------------43 表3-3.2 化合物25~36的結構與PDK1 IC50值----------------45

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