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研究生：	古書吉 Shu-Ji Gu
論文名稱：	B-RAF激酶分子化合物之嵌合計算研究 Docking Computation of B-RAF Kinase-Ligand Complexes
指導教授：	孫英傑 Sun, Ying-Chieh
學位類別：	碩士 Master
系所名稱：	化學系 Department of Chemistry
論文出版年：	2011
畢業學年度：	99
語文別：	中文
論文頁數：	104
中文關鍵詞：	分子嵌合、B-RAF
英文關鍵詞：	Docking, B-RAF
論文種類：	學術論文
相關次數：	點閱：77 下載：4
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查詢本校圖書館目錄查詢臺灣博碩士論文知識加值系統勘誤回報

EGFR(Epidermal Growth Factor receptors)路徑與調節細胞的生長、生殖與凋零的現象有很大相關性。B-RAF 位於EGFR路徑中，是目前癌症細胞中最常被突變的蛋白質激酶之一。在黑色素瘤、卵巢癌、甲狀腺癌與直腸癌都顯示有大量B-RAF 突變的現象。
本研究中，主要用分子嵌合計算來研究 B-RAF抑制劑。我們首先利用資料庫中B-RAF 結晶構型進行計算，並且與已知的實驗數據去比對其相關性，看是否能再現實驗結果。之後選擇出5個 B-RAF抑制劑複合物做交叉分子嵌合計算，並且去探討當加入蛋白質活性中心附近的胺基酸在可變動的情況下，對於再現不同抑制制時的影響。
在虛擬篩選的部份，首先用標準方法計算enrichment factor，將10個已知的活性分子與990個decoys 一起做嵌合計算，並且藉由胺基酸可變動的方式，探討是否能提高(影響) enrichment factor的結果，結果顯示在固定支鏈與部分動支鏈的結果差異並不明顯。
最後利用高速虛擬篩選，篩選ZINC資料庫中的其中400000個分子去搜尋出與B-RAF有最佳作用力的分子，並且列出最好的100個分子。希望這些計算的結果將有助於實驗學家在設計B-RAF的抑制劑上的設計與搜尋。

總目錄
圖目錄   -------------------------------------   IV
表目錄   -------------------------------------   VI
中文摘要   ----------------------------------  VIII
英文摘要(Abstract)   ------------------------    IX

第一章      緒論   -----------------------------   1
1-1    前言   ---------------------------------------    2
1-2    B-RAF 與MAPK 訊息傳遞路徑   ------------------    4
1-3    與B-RAF 突變相關的癌症   ---------------------    6
1-4    B-RAF抑制劑   --------------------------------    7
1-5    B-RAF 結構   ----------------------------------    9
1-6    B-raf 抑制劑的結構與IC50值   ------------------   11
1-7    分子嵌合(Docking)   ---------------------------   14
1-8    研究目標   ------------------------------------   16

第二章  理論與設定   -------------------------   17
2-1    GOLD   ----------------------------------------   18
2-2      評分函數( Fitness Function)   -----------------   19
2-2-1    氫鍵作用力   -------------------------   20
2-2-2        金屬原子產生的作用力   ---------------  21
2-2-3        親油性(lipophilic)   ----------------   22
2-2-4        Rotatable-bond Freezing   -----------    23
2-2-5    分子間的碰撞(Clash)與分子內的扭角
 (Torsion)   -------------------------   24
   2-2-6    共價鍵 與約束力(constrain)   --------  26
2-3    基因演算法(Genetic Algorithm,GA)   ------------   27
2-4    搜索效率(search efficiency)   -----------------   29
2-5    胺基酸支鏈(side chain)設定   ------------------   30

第三章  實驗   -----------------------  32
3-1    分析方法   ------------------------------------   33
3-2    再現已知IC50實驗值的結晶結構   ---------------   34
3-3    設定可動胺基酸支鏈的交叉分子嵌合   ------------   42
3-4    B-raf結構的enrichment factor  ----------------   48
3-5    高速篩選ZINC化學分子資料庫   -----------------   52


第四章  計算結果與討論   ------------------   54
4-1    再現B-RAF 35個活性分子與結果   ---------------   55
4-2    B-RAF設定可動胺基酸支鏈的交叉分子嵌合   -------  57
       4-2-1  蛋白質支鏈固定不動結果分析   -----------   59
       4-2-2  LYS483與LYS591可做位向搜尋的交叉嵌合  -   61
       4-2-3  LYS483、TRP531、LYS591與LEU596可做支
               鏈位向搜尋的交叉嵌合   ----------------   63
4-3    B-raf結構的enrichment factor   ---------------   66
       4-3-1   分析/討論不同胺基酸支鏈的設定   -------   67
       4-3-2   分析/討論五個結晶構形的結果   ---------   75
4-4    高速虛擬篩選結果   ----------------------------   80
        4-4-1   前100分子結構 -----------------------   83
        4-4-2   篩選的前10個分子   ------------------   93

第五章   結論   ----------------------  99
參考文獻   --------------------------- 101
                                

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