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|標題:||Ortho effects in quantitative structure-activity relationships for acetylcholinesterase inhibition by aryl carbamates||作者:||Lin, G.
|關鍵字:||acetylcholinesterase;QSAR;Ortho effects;carbamate inhibitors;structure-reactivity relationships;steady-state kinetics;cholesterol;esterase;molecular recognition;strengths;mechanism;site;cholinesterases;prediction;substrate||Project:||Journal of Enzyme Inhibition and Medicinal Chemistry||期刊/報告no：:||Journal of Enzyme Inhibition and Medicinal Chemistry, Volume 19, Issue 5, Page(s) 395-401.||摘要:||
Ortho-substituted phenyl-N-butyl carbamates (1-9) are characterized as "pseudo-pseudo-substrate" inhibitors of acetylcholinesterase. Since the inhibitors protonate at pH 7.0 buffer solution, the virtual inhibition constants (K-i's) of the protonated inhibitors are calculated from the equation, -logK(i)' = -logK(i) - logK(b). The logarithms of the inhibition constant (K-i), the carbamylation constant (k(c)), and the bimolecular inhibition constant (k(i)) for the enzyme inhibitions by carbamates 1-9 are multiply linearly correlated with the Hammett para-substituent constant (sigma(p)), the Taft-Kutter-Hansch ortho steric constant (E-S), and the Swan-Lupton ortho polar constant (F). Values of rho, delta, and f for the -logK(i)-, logk(c)-, and logk(i)-correlations are -0.6, -0.16, 0.7; 0.11, 0.03, -0.3; and -0.5, -0.12, 0.4, respectively. The K-i step further divides into two steps: 1) the pre-equilibrium protonation of the inhibitors, K-b step and 2) formation of a negatively charged enzyme-inhibitor Michaelis-Menten complex virtual inhibition, K-i' step. The K-i step has little ortho steric enhancement effect; moreover, the k(c)step is insensitive to the ortho steric effect. The f value of 0.7 for the K-i step indicates that ortho electron-withdrawing substituents of the inhibitors accelerate the inhibition reactions from the ortho polar effect; however, the f value of 20.3 for the k(c)step implies that ortho electron-withdrawing substituents of the inhibitors lessen the inhibition reactions from the ortho polar effect.
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