臺灣博碩士論文加值系統

本論文以一-醯氧-三-甲基磺酸氧苯類抑制劑對乙醯膽鹼酯酵素、丁醯膽鹼酯酵素及膽固醇酯酵素反應中酵素-抑制劑複合體抑制常數( pKI )進行定量結構活性關係( QSAR )分析。將酵素-抑制劑複合體的動力學常數─抑制常數(KI )對不同取代基之電子效應常數( σ* )、疏水性常數( π )以及立體效應常數( ES )作線性迴歸分析，並探討在此類化合物上置換不同取代基，對抑制三種酵素的效果有何影響，使我們對此類抑制劑的抑制機理有更深一層的認識，也分析一-醯氧-三-甲基磺酸氧苯類抑制劑在三種不同酵素酵素中的差異。
第二部分使用Gaussian 03理論計算軟體計算一-醯氧-三-甲基磺酸氧苯類抑制劑的能量與電荷，搭配NMR光譜結果，對抑制劑上不同取代基之電子效應常數( σ* )、立體效應常數( ES )以及疏水性常數( π )作定量結構活性關係( QSAR )分析，推測出三種不同酵素對此類抑制劑的反應快慢與安定性，也與前述部份研究相互應證。
目前市面上的藥劑開發研究，在新的藥物設計合成方面，主要先從實驗分析與預先模擬藥物反應是否發生，此一部分研究在藥物設計開發上是極重要的環節。若能有效的分析藥劑的性質及可行性，對未來實驗室藥劑的設計合成上可以帶來幫助、提高效益，期許未來可以應用在更廣的層面，為人類帶來多有助益的新藥研發訊息。

目錄
第一章　 緒論 1
1-1　研究動機與目的 1
1-2　定量結構活性關係(QSAR) 2
1-2.1　定量結構活性關係 2
1-2.2　疏水性 4
1-2.3　電子效應 6
1-2.4　立體效應 8
1-2.5　Hammett Equation ─σmeta 和σpara 10
1-2.6　Taft equation ─脂肪族的極性效應 15
1-3酵素介紹 19
1-3.1　酵素特性 19
1-3.2　乙醯膽鹼酯酵素 21
1-3.3　丁醯膽鹼酯酵素 25
1-3.4　AChE與BChE催化酯類受質的水解反應 27
1-3.5　膽固醇酯酵素 29
1-3.6　CEase催化受質的水解反應 31
1-4　酵素動力學原理 33
1-4.1　抑制劑原理 33
1-4.2　可逆抑制劑 37
第二章　材料與方法 44
2-1　抑制劑的合成步驟 44
2-2　儀器設備 48
2-3　 抑制劑的光譜數據 49
2-4　酵素動力學材料與方法 53
2-4.1　乙醯膽鹼酯酵素部份 53
2-4.2　丁醯膽鹼酯酵素部份 53
2-4.3　膽固醇酯酵素部份 54
2-5　動力學實驗方法與數據處理 57
2-5.1　停時驗析 (Stop-Time Assay)之操作步驟 57
2-5.2　可逆競爭性抑制反應 59
第三章　一-醯氧-三-甲基磺酸氧苯類化合物之定量結構活性分析( QSAR )結果 60
3-1　乙醯膽鹼酯酵素QSAR 結果 61
3-1.1　一-醯氧-三-甲基磺酸氧苯類化合物酵素動力學數據及QSAR分析 61
3-1.2　抑制劑a-g 抑制乙醯膽鹼酯酵素動力學數據與各項參數之單參數線性迴歸分析 63
3-1.3抑制劑a-g 抑制乙醯膽鹼酯酵素動力學數據與各項參數之雙參數線性迴歸分析 66
3-1.4抑制劑a-g 抑制乙醯膽鹼酯酵素動力學數據與各項參數之三參數線性迴歸分析 69
3-1.5抑制劑a-g 抑制乙醯膽鹼酯酵素與其QSAR影響參數(取代基電子效應常數(σ*)、疏水性常數(π)、立體常數 (Es))對其pKI之線性迴歸結果分析 70
3-2　丁醯膽鹼酯酵素QSAR 結果 75
3-2.1一-醯氧-三-甲基磺酸氧苯類化合物酵素動力學數據及QSAR分析 75
3-2.2抑制劑a-g 抑制丁醯膽鹼酯酵素動力學數據與各項參數之單參數線性迴歸分析 77
3-1.3抑制劑a-g 抑制丁醯膽鹼酯酵素動力學數據與各項參數之雙參數線性迴歸分析 80
3-2.4抑制劑a-g 抑制丁醯膽鹼酯酵素動力學數據與各項參數之三參數線性迴歸分析 83
3-2.5抑制劑a-g 抑制丁醯膽鹼酯酵素與其QSAR影響參數(取代基電子效應常數(σ*)、疏水性常數(π)、立體常數 (Es)對其pKI之線性迴歸結果分析 84
3-3　膽固醇酵素QSAR 結果 89
3-3.1一-醯氧-三-甲基磺酸氧苯類化合物酵素動力學數據及QSAR分析 89
3-3.2抑制劑a-g 抑制膽固醇酯酵素動力學數據與各項參數之單參數線性迴歸分析 91
3-3.3抑制劑a-g 抑制膽固醇酯酵素動力學數據與各項參數之雙參數線性迴歸分析 94
3-2.4抑制劑a-g 抑制膽固醇酯酵素動力學數據與各項參數之三參數線性迴歸分析 97
3-3.5抑制劑a-g 抑制膽固醇酵素與其QSAR影響參數(取代基電子效應常數(σ*)、疏水性常數(π)、立體常數 (Es))對其pKI之線性迴歸結果分析 98
3-4　一-醯氧-三-甲基磺酸氧苯類抑制劑抑制乙醯膽鹼酯酵素、丁醯膽鹼酯酵素及膽固醇酵素的定量結構活性分析結果整理表 103
第四章　Gaossian03理論計算在化學方面的應用 105
4-1　理論計算原理簡介 106
4-1.1　量子化學 107
4-1.2　計算化學的理論 109
4-1.3　全初始法（ab initio Method） 110
4-1.4　密度泛函理論 ( Density functional Theory，DFT )112
4-1.5　B3LYP理論 116
4-1.6　基底函數組 ( Basis Set ) 118
4-1.7　分裂基底 (Split basis set) 122
4-1.8　極化函數 (Polarized basis set) 123
4-1.9　擴散函數 (Diffuse function) 124
4-1.10　Gaussian 03 軟體計算 125
4-1.11　模型正確性及方法正確性 126
4-1.12　Gaussian 03 模組中建立計算 128
4-2　本論文採用的計算方法及實驗目的 131
4-3　抑制劑之理論計算結果與分析 132
4-3.1　一-醯氧-三-甲基磺酸氧苯類抑制劑 a-g的理論計算結果 132
4-3.2　一-醯氧-三-甲基磺酸氧苯類抑制劑理論計算數據與動力學數據的分析結果 141
4-3.3　一-醯氧-三-甲基磺酸氧苯類抑制劑最低能量、偶極矩與取代基常數QSAR分析結果 158
第五章　結論 165
參考文獻....................................................170

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