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研究生: 邱映霖
Chiu Ying-lin
論文名稱: 秋水仙鹼類似化合物與微管蛋白複合體之分子動力學模擬:結合能計算
Molecular Dynamics Simulation of Complexes of Colchicine Binding Site Ligands and Tubulin: Binding Energy Calculation
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: 2008
畢業學年度: 96
語文別: 中文
中文關鍵詞: 秋水仙鹼微管蛋白分子動力學模擬結合能計算
英文關鍵詞: Colochicine, Tubulin, Molecular Dynamics Simulation, Binding Energy
論文種類: 學術論文
相關次數: 點閱:155下載:0
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  • 已知秋水仙鹼(colchicines)會與微管蛋白(tubulin)結合而干擾微管蛋白聚合之動力學,同時已有實驗證實此效應具有對抗癌症的效果。我們有興趣在於設計此類作用於秋水仙鹼結合位置(colchicine binding site)更好的藥物分子,在本篇研究中,我們利用全原子(all-atom)的分子動力學模擬方法,針對一些作用在微管蛋白其秋水仙鹼結合位置上的藥物分子研究,同時以MM-PBSA / MM-GBSA方法計算結合能。總共計算秋水仙鹼分子及其13個類似分子,部分分子之能量與已知實驗的抑制活性數值IC50值具有好的相關性。根據首先計算十個化合物的計算結果,我們更進一步設計三個新的藥物分子,此三個新設計分子皆較其他分子有更穩定之結合能。我們分析及討論幾個影響結合能計算之因素,包括: 修改化合物官能基的影響、蛋白質結合位置附近的胺基酸個別對總結合能的貢獻,以及分子間作用力的分析與討論,得到幾個修改官能基的建議包括: (1)官能基R4的位置置換為OH基,此OH基會與胺基酸α179THR產生穩定氫鍵,穩定化合物與微管蛋白的結合。(2)官能基R5的位置修改成具有苯環的酮類官能基,其官能基置換可與胺基酸β352LYS產生氫鍵,同時增加與胺基酸β248LEU之間的凡得瓦作用能,以及促進與β251ASP/β252ASP形成氫鍵。這些結果以及其他分析將有助於未來設計更好的藥物分子。

    Ligands which bind at the colchicine site of tubulin, interfering with tubuline polymerization dynamics, have been showed to have anti-cancer effects. We are interested in drug design of a series of ligands binding at the colchicines binding site of tubulin. We used all-atom molecular dynamics simulation method to examine a number of ligands, binding with tubulin, using MM-PBSA/MM-GBSA approach. The calculated binding energies are reported. The calculated binding energies are in good accord with the available IC50 values of some ligands. Based on the results of the first-examined 10 ligands, we further designed 3 new ligands. Computations for these 3 ligands showed that the binding of these 3 ligands with tubulin are more stable than other ligands. Functional group substitution effects of this series of ligands, contributions of residues at the binding site of protein, correlation with available experimental results, and other factors are analyzed and discussed. These discussions lead to several suggestions of functional group substitutions, including (1) substitution of OH group at R4 site, which can form a hydrogen bond with the amino acid α179THR. (2) substitution of a carbonyl group with benzene ring (see text) at R5 site, which can form a hydrogen bond with the residue β352LYS, increase the vdw interaction with the residue β248LEU, and enhance formation of hydrogen bond with the residues β251ASP/β252ASP. These results and analysis should be of aid in designing better ligands.

    第一章 緒論 1-1 序 1-2 藥物分子作用於微管蛋白及其秋水仙鹼結合位置 1-3 研究目標 第二章 方法 2-1 分子動力學模擬 2-1-1 分子動力學模擬理論 2-1-2 分子動力學模擬設定 2-2 與微管蛋白作用之化合物 2-3 能量計算 2-3-1 The molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA)理論及設定 2-3-2 個別胺基酸能量貢獻及The molecular mechanics/Generalized Born surface area (MM-GBSA)理論及設定 2-4 原子擾動計算及氫鍵計算設定 第三章 結果與討論 3-1 化合物與微管蛋白複合體之模擬 3-1-1 模擬的結構偏差 3-1-2 微管蛋白其胺基酸二級結構之探討 3-2 能量結果 3-3 藥物分子之IC50值與能量相關 3-3-1 利用個別胺基酸作用力判斷秋水仙鹼之IC50值較小因素 3-3-2 利用個別胺基酸作用力判斷podophyllotoxin之IC50值較大因素 3-4 胺基酸與分子間氫鍵作用力分析 3-4-1 Deactamidocochicine (DAAC)、deacetylcolchicine (NH2DAAC)模擬之氫鍵結果 3-4-2 秋水仙鹼模擬之氫鍵結果 3-4-3 Podophyllotoxin模擬之氫鍵結果 3-4-4 本實驗化合物模擬之氫鍵結果 3-5 官能基的效應 3-5-1 疏水效應 3-5-2 R1、R2、R3官能基 3-5-3 R4官能基 3-5-4 R5官能基 3-6 新取代基分子的預測 3-6-1 新取代基分子L00預測 3-6-2 新取代基分子L0A及L0B預測 第四章 結論 第五章 附錄與參考資料 附錄一 與國家衛生研究院合作的71個藥物分子 附錄二 各個化合物計算資料 參考資料

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