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研究生： 許正昌
論文名稱： 運用GOLD程式進行具吲哚環的抗微管蛋白化合物之對位計算研究
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： 2008
畢業學年度： 96
語文別： 中文
論文頁數： 76
中文關鍵詞： 微管蛋白 癌症 對位研究
論文種類： 學術論文
相關次數： 點閱：72  下載：0 
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    • 在尋找更好的抗微管蛋白聚合的抑制劑的努力中，最近的實驗測量71個化合物的抗胃癌細胞株的IC50值，這一系列的化合物主要是以TMP、吲哚環(indole ring)和C=O當做橋接鍵為組合片段，在吲哚環上做不同官能基的取代(見下圖)。在本研究中，我們利用GOLD軟體去計算這一系列的化合物與微管蛋白結合的構型與能量，計算結果發現大多數化合物的構型跟微管蛋白結晶結構中的鬼臼毒素(Podophyllotoxin)很類似，從評分函數中可發現決定這類結合模式的主要穩定作用力為凡得瓦作用力，我依此結合模式去設計新的衍生物。在R1~R6測試接不同官能基可發現，(1) R1、R2、R4只適合去接一個重原子為限的官能基，(2) R3可接Et這種非極性官能基，R6可以接類似TMP的官能基。除此之外，從這些計算結果中發現兩個重要的氫鍵作用力，一個是吲哚環上的N-H會跟THR173:O產生氫鍵，另一個是在R6末端接類似TMP的官能基，TMP上中間OMe的氧會跟LYS684產生強烈的氫鍵作用力，這兩個氫鍵作用力對於穩定POD-like構型有一定的貢獻，希望這些發現對於藥物設計能有所幫助。

    圖目錄-------------------------------------------Ⅲ 表目錄-------------------------------------------Ⅴ 摘要---------------------------------------------Ⅶ Abstract-----------------------------------------Ⅷ 第一章 緒論-------------------------------------1 1-1 前言----------------------------------------2 1-2 微管與癌症的關係--------------------------3 1-3 以微管蛋白為標靶的抗有絲分裂藥物------------5 1-4 Docking--------------------------------------7 1-5 研究目標------------------------------------8 第二章 理論與方法------------------------------10 2-1 GOLD--------------------------------------11 2-2 Scoring Function------------------------------12 2-2-1 凡得瓦-----------------------------------------13 2-2-2 氫鍵-------------------------------------------14 2-2-3 Torsional Strain Energy----------------------------16 2-3 基因演算法---------------------------------17 2-4 計算之前置處理與docking的設定--------------19 2-5 分析方法-----------------------------------20 2-6 Tubulin-ligand 複合體已知實驗3D結構之再現---21 第三章 計算結果與討論--------------------------22 3-1 71個化合物的fitness score--------------------23 3-2 71個化合物的結合模式-----------------------26 3-3 分析各個結合模式的成因及特性---------------28 3-3-1 POD-like---------------------------------------29 3-3-2 顛倒-------------------------------------------35 3-3-3 TMP往前--------------------------------------39 3-3-4 反POD----------------------------------------43 3-4 R1~R6接官能基的結合模式跟能量上的改變-----45 3-5 其他衍生物之計算---------------------------60 3-6 將結果跟文獻比較---------------------------65 3-7 GOLD跟Autodock的結果比較-----------------68 第四章 結論------------------------------------71 第五章 參考文獻--------------------------------73 附錄---------------------------------------------77 圖目錄 圖1 微管的組成及形狀與大小--------------------------3 圖2 在有絲分裂中，染色體被拉向兩極-------------------4 圖3 左圖為Colchicine，右圖為Podophyllotoxin的結構-------6 圖4 CA-4跟71個化合物的基本組成--------------------8 圖5 Colchicine位於蛋白質中的β1位置上----------------9 圖6 氫鍵的計算方法之距離跟角度---------------------15 圖7 GA的詳細流程圖-------------------------------18 圖8 X-ray跟docking的結果比較圖---------------------21 圖9 由左而右分別是POD-like、顛倒、TMP往前、反POD的 構型-------------------------------------------27 圖10 POD-like構型之常見氫鍵作用力-------------------33 圖11 POD-like構型之3D結構圖------------------------34 圖12 顛倒構型時常見的氫鍵作用力---------------------37 圖13 顛倒構型時附近疏水效應-------------------------38 圖14 TMP往前構型時R5接官能基的位置---------------40 圖15 TMP往前構型常見的氫鍵作用力------------------41 圖16 TMP往前構型在binding site的情況----------------42 圖17 反POD構型的在binding site的情況----------------44 圖18 各個結合模式在不同pIC50的範圍所含的化合物數目-45 圖19 R1接官能基的位置會受到R3所影響---------------46 圖20 R3接OPr跟POD的比較圖------------------------48 圖21 R3固定接OMe，R2的空間大小--------------------49 圖22 R1接F之POD-like構型--------------------------51 圖23 R1接F，R3接OMe的化合物跟POD比較圖----------52 圖24 R5接官能基後的3D空間圖-----------------------55 圖25 化合物 46之R5環的擺放處----------------------56 圖26 R6接Pr，indole ring上的N換成O跟S，三個化合物的 疊合圖-----------------------------------------58 圖27 化合物 62在binding site的3D空間圖--------------58 圖28 化合物 A24的氫鍵產生位置----------------------63 圖29 重原子數跟VDW作用力的相關圖-----------------64 圖30 POD之6點藥效集團的位置-----------------------65 圖31 TMP傾斜角度的差別----------------------------67 圖32 R6接的官能基和LYS684產生氫鍵-----------------67 表目錄 表1 71個化合物的docking結果-----------------------23 表2 各種結合模式所占的比率---------------------26 表3 依重原子數來排列，有詳細的凡得瓦作用力和S(int) --29 表4 POD-like構型時所觀察到的氫鍵位置以及大小-------32 表5 顛倒跟POD-like的VDW的比較-------------------35 表6 顛倒構型的化合物所觀察到的氫鍵位置以及大小----36 表7 TMP往前跟POD-like構型的VDW作用力-----------39 表8 TMP往前構型所產生的氫鍵作用力跟大小----------41 表9 反POD跟POD-like構型的VDW比較---------------43 表10 R1~R6均不接官能基之顛倒和POD-like構型比較----46 表11 R3設計官能基的結果----------------------------47 表12 只在R2接官能基的比較--------------------------49 表13 R3固定接OMe，R2接不同官能基的結果------------50 表14 R3固定接Et，R2接不同官能基的結果--------------50 表15 R1接F跟R1~R6不接取代基的比較----------------52 表16 只在R4接取代基的結果--------------------------53 表17 R3、R4接取代基的結果---------------------------53 表18 R5接直鏈官能基的結果--------------------------54 表19 分別在R6接Me、Et、Pr的結果---------------------57 表20 新設計的衍生物結構--------------------------60 表21 新設計的衍生物之docking詳細內容---------------62 表22 GOLD與Autodock結合模式的比較----------------68

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