研究生: |
李德傑 Lee, Der-Jei |
---|---|
論文名稱: |
小分子與蛋白質結合複合體之電腦模擬計算研究 Computer Simulation of Protein-ligand Complexes: Docking and MD Simulations |
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: | 2017 |
畢業學年度: | 105 |
語文別: | 中文 |
論文頁數: | 127 |
中文關鍵詞: | GSK-3β 蛋白質激酶 、IDO 、半乳糖苷酶 、分子嵌合 、豐富指數 、虛擬篩選 、分子資料庫 |
英文關鍵詞: | GSK-3β, IDO, thermodynamic integration, MD simulation, Galactosidase, virtual screening, docking |
DOI URL: | https://doi.org/10.6345/NTNU202202616 |
論文種類: | 學術論文 |
相關次數: | 點閱:136 下載:0 |
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本研究中,我們使用了電腦模擬技術研究有潛力發展出藥物的蛋白質-小分子複合體,特別專注於研究競爭型的小分子抑制劑。熱力學積分及分子嵌合計算是本論文所使用的兩個主要計算方法,我們利用這兩個計算方法研究了三個蛋白質系統,介紹如下:
肝醣合成酶激酶-3(GSK-3) 我們藉由熱力學積分及分子嵌合去研究新型態的GSK-3β 抑制劑。首先從小分子資料庫中收集數百萬個化合物並進行嵌合計算篩選化合物,並選擇5個高評分的分子進行熱力學積分的計算,估計其結合強度及預測其結合位向,計算所得結合強度較強的分子將建議給實驗學家進行酵素實驗。在計算的5個分子中,預測了1個化合物的Kd值接近M,預測的結合位向結果可進一步運用於類似物抑制劑的開發上。
半乳糖苷酶(Galactosidase) 我們藉由嵌合計算去計算幾種已知抑制劑並協助設計產生更好的衍生物。首先,先預測了已知抑制劑的結合位向,藉由疊圖與氫鍵分析分析半乳糖苷酶在活性位置的作用情形。之後,進一步地設計了13個相關的衍生物分子,並推薦了1個分子給實驗學家做酵素實驗。
吲哚胺-吡咯2,3-雙加氧酶(IDO) 我們使用了共價嵌合計算去輔助設計具有共價鍵的抑制劑。總共彙整了3類抑制劑分子共38種化合物並使用共價嵌合計算來進行排序,這些化合物的排序有助於開發類似的共價抑制劑。
關鍵字: GSK-3β 蛋白質激酶、IDO、 半乳糖苷酶、分子嵌合、豐富指數、虛擬篩選、分子資料庫
In this study, we utilized computer simulation to investigate protein-ligand complexes that have potential to develop drugs. We focused on identifying new small molecule inhibitors with competitive mechanism. Thermodynamic integration (TI) MD simulation and molecular docking computation are two main computational methods for these investigations. The three examined protein systems are described below.
GSK-3β kinase We aimed to identify new type GSK-3β kinase inhibitors by using docking computation and TI MD simulation. First, docking computations was carried out to screen millions of compounds. Selected top-ranked compounds are subject to TI-MD simulation in order to refine their estimated binding affinity with GSK3 kinase and predict their binding modes. Compounds of strong affinity were suggested to further experimental validation. Among examined 5 compounds, the computations predicted 1 compound with strong affinity. The predicted binding modes should aid in further development of analog inhibitors.
Galactosidase We utilized docking computation to aid in design of analogous, better inhibitors of a few known inhibitors. The binding modes were first examined and their interactions with galactosidase were analyzed. Among 13 designed derivative compounds, the computation predicted 1 compounds enhancing the inhibition. One compound was subject to experimental assay and exhibited enhanced inhibition.
Indoleamine 2,3-dioxygenase (IDO) For this enzyme, we used covalent docking to aid in design of covalent inhibitors. Several classes of potential covalent inhibitors in total of 38 compounds were investigated. Ranking of these compounds should be useful for development of effective, analogous covalent inhibitors of the examined compounds.
Keywords : GSK-3β, IDO, thermodynamic integration, MD simulation, Galactosidase, virtual screening, docking
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