臺灣博碩士論文加值系統

本論文主要研究鄰、間、對位苯雙取代氨基甲酸化合物不同碳鏈的取代對乙醯膽鹼酯酵素、丁醯膽鹼酯酵素、脂肪酵素、膽固醇酵素等四種酵素，皆可產生抑制作用，為了瞭解抑制劑的活性(activity)，應先瞭解抑制劑結構的特質，可以幫助我們瞭解抑制劑在各反應系統反應狀況的特性。使用Gaussian 09計算軟體來進行此抑制劑分子結構的幾何優化以及逐步轉動氨基甲酸C-N鍵，對抑制劑進行構形分析，探討改變碳鏈的各種抑制劑之最低能量構形、二面角、電荷和旋轉障礙能障的狀況。並將Gaussian 09理論計算出的數值與σ*、π、Es和抑制劑常數作線性迴歸，來檢視預測其相關性。
乙醯膽鹼酯酵素的pKi與最低能量呈現正相關，當能量越高其pKi值越大，故化合物a、d 、e抑制效果最佳；脂肪酵素的pKi與能量呈現負相關，當能量越低趨於穩定時，其pKi值越大，故化合物c、f、i抑制效果越佳。 BChE的pKi與其氨基甲酸上的碳之電荷成反比關係，表示當取代基的推電子效應越好時，抑制效果越佳，故化合物c、f、 i抑制效果最佳，與實驗符合。 抑制劑氨基甲酸上碳的化學位移與丁醯膽鹼酯酵素的抑制常數有高度定量線性關係；抑制劑旋轉能障與乙醯膽鹼酯酵素的抑制常數呈現負相關，當旋轉能障越低時，越容易越過狹窄溝進入活化區，抑制效果越佳。

第一章 緒論 1
1-1研究動機與目的 1
1-2酵素特性 2
1-3 酵素簡介 3
1-3.1乙醯膽鹼酯酵素 3
1-3.2丁醯膽鹼酯酵素 6
1-3.3膽固醇酯酵素 10
1-3.4脂肪酵素 11
1-4 定量結構活性關係 15
1-4.1 原理 15
1-4.2影響定量結構活性關係之参數 16
第二章 設備與方法 23
2-1電腦軟體 23
2-2 Gaussian09 操作方法 23
Part1 結構幾何優化(DFT 6-311g(d)): 23
Part2逐步旋轉化學鍵方法(HF 6-311g(d)): 24
第三章 Gaussian09軟體在化學方面的應用 25
3-1 概述 25
3-2 理論計算原理簡介---量子化學 26
3-3 哈特里-福克(Hartree-Fock)方程式 27
3-3.1簡述 27
3-3.2背景 28
3-3.3方程的推導 29
3-3.4方程式的解與自洽場方法 32
3-4 密度泛函理論(Density Function Theory，DFT ) 35
3-4.2基底函數組 ( Basis Set ) 39
3-6 構形分析(conformational analysis) 45
3-6.1分子動力學(molecular dynamics) 45
3-6.2逐步轉動化學鍵(stepwise rotation of bonds) 46
3-7受限的旋轉（restricted rotation) 47
3-8 研究架構 50
3-9 量化計算 50
第四章 結果與討論 51
4-1 Gaussian 09理論計算數據與討論 51
4-1.1抑制劑能量與QSAR參數之線性迴歸 54
4-1.2抑制劑最低能量與動力學常數分析結果討論 60
4-1.3理論計算電荷和動力學常數分析結果討論 63
4-1.4氨基甲酸上C的化學位移和動力學常數分析結果討論 69
4-2鄰、間、對位苯雙取代氨基甲酸化合物構形分析 72
4-3理論計算數據探討分析結果 103
4-3.1鄰位抑制劑的旋轉能障與QSAR參數之線性迴歸 103
4-3.2 間位抑制劑的旋轉能障與QSAR參數之線性迴歸 111
4-3.3 對位抑制劑的旋轉能障與QSAR參數之線性迴歸 119
4-4 抑制劑的旋轉能障與抑制常數之線性迴歸 127
第五章 結論 136
參考文獻 138

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