Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/49515
標題: 甲夫方程式研究1,3,5-參-烷基氨基甲酸-苯抑制膽鹼酯酵素之線性自由能
Linear Free Energy Relationships for Cholinesterase Inhibition by 1,3,5-Tri-N-Alkylcarbamylbenzene Based on Jarv's Equation
作者: 林家立
關鍵字: 化學類
基礎研究
linear free energy relationship
線性自由能關係式
定量結構活性關係式
酵素抑制
酵素動力學
氨基甲酸
膽鹼酯酵素
quantitative structure activity relationship
enzymeinhibition
enzyme kinetics
carbamate
cholinesterase
摘要: 甲夫方程式研究1,3,5-參-烷基氨基甲酸-苯抑制膽鹼酯酵素之線性自由能本計畫我們設計合成1,3,5-參-氮-烷基氨基甲酸苯為乙醯膽鹼酯酵素及丁醯膽鹼酯酵素之參-位置抑制劑。這些抑制劑可能賭住此兩種酵素之醯基鍵結位置(acyl binding site),陰離子區域(anionic site),及周邊陰離子區域(peripheral anionic site)。這些抑制劑可能像其他氨基甲酸化合物皆是此兩種酵素之類受質抑制劑。這些抑制反應之抑制劑常數(Ki),氨基甲酸化常數(kc),及總抑制劑常數(ki = kc / Ki)將藉由最小平方差之非線性曲線逼近(nonlinear curve fitting)計算其吸收值-時間圖而得。這些抑制反應之pKi,logkc,及logki 可能與抑制劑上取代基之哈密特氏常數(Hammett’s ),鐵夫氏立體常數(Taft’s Es),及漢司氏疏水常數(Hansch’s )存在著甲夫氏(Järv’s)方程式(pKi,logkc,或logk i= + Es + )之多重參數(multiple parameters)之線性自由能關係式。這些多重參數線性逼近圖形之斜率(逼近後求得之參數)可以分辨出上述效素抑制反應之機理。例如若哈密特氏反應常數(Hammett’s )大於零代表酵素活性位置之絲氨酸攻擊抑制劑之三個氨基甲酸之一形成帶負電荷之酵素-抑制劑四面體中間物。另一方面抑制劑之三個氨基甲酸取代基的第二個可能與酵素之周邊陰離子區域形成非共價鍵結合。此類結合之抑制劑疏水靈敏度參數()可能大於零。最後抑制劑取代基之立體靈敏度參數()可能大於零代表抑制劑之壅塞之取代基阻礙反應若值大小於零代表抑制劑之壅塞之取代基加速反應。這些抑制劑的最佳構形可藉由MP4 (Gaussian 程式)計算之構形分析(conformational analysis)求得並與酵素之X-光結晶進行模擬其結合機理。
Linear Free Energy Relationships for Cholinesterase Inhibition by1,3,5-tri-N-alkylcarbamylbenzene Based on Järv's EquationIn this proposal, we plan to synthesize 1,3,5-tri-N-alkylcarbamylbenzenes as triple-siteinhibitors of both acetylcholinesterase and butyrylcholinesterase. These inhibitors may potentiallyblock the acyl binding, anionic, and peripheral anionic sites of both enzymes. These inhibitorsmay be also characterized as the pseudo substrate inhibitors of both enzymes like other carbamateinhibitors. The inhibition constant (Ki), carbamylation constant (kc), and overall inhibitionconstant (ki = kc /Ki) for these inhibition reactions will be also calculated from nonlinear leastsquares analysis of the absorption-time plot. For these inhibition reactions, pKi, log kc, and log ki,may exist multiple-parameters linear free energy relationships with substituted constants such asHammett constant (), Taft steric constant (Es), and Hansch hydrophobicity constant () from Järvequation (pKi, log kc, or log ki = + Es + ). The slopes (parameters from the fitting) fromthese multiple parameters linear correlations may indicate what reaction mechanisms of theseinhibitions are. For example, one carbamyl carbon of the inhibitors is attacked by the catalyticserine of the enzyme then formation of the negatively charged tetrahedral intermediates if theHammett reaction constant () is greater than zero. On the other hand, another carbamyl moiety ofinhibitors may bind to the peripheral anionic site of both enzymes. For this binding, sensitivity onthe hydrophobicity of inhibition () is also expected to be greater than zero. Finally, sensitivity onsteric effect of the substituent for the inhibition () may be greater than zero if the inhibition isretarded by an inhibitor with a bulky substituent or less than zero if the inhibition is accelerated byan inhibitor with a bulky substituent. The minimized conformations of these inhibitors may beobtained from the conformational analysis of these inhibitors by MP4 in the Gaussian program thenthese conformations are fitted into the X-ray structures of both enzymes to model the possiblebinding between these inhibitors and both enzymes.
URI: http://hdl.handle.net/11455/49515
其他識別: NSC99-2113-M005-012
文章連結: http://grbsearch.stpi.narl.org.tw/GRB/result.jsp?id=2100784&plan_no=NSC99-2113-M005-012&plan_year=99&projkey=PA9907-0714&target=plan&highStr=*&check=0&pnchDesc=%E7%94%B2%E5%A4%AB%E6%96%B9%E7%A8%8B%E5%BC%8F%E7%A0%94%E7%A9%B61%2C3%2C5-%E5%8F%83-%E7%83%B7%E5%9F%BA%E6%B0%A8%E5%9F%BA%E7%94%B2%E9%85%B8-%E8%8B%AF%E6%8A%91%E5%88%B6%E8%86%BD%E9%B9%BC%E9%85%AF%E9%85%B5%E7%B4%A0%E4%B9%8B%E7%B7%9A%E6%80%A7%E8%87%AA%E7%94%B1%E8%83%BD
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