Quantitative structure-activity relationships for the pre-steady state acetylcholinesterase inhibition by carbamates.
4-Nitrophenyl-N-substituted carbamates (1) are characterized as pseudosubstrate inhibitors of acetylcholinesterase. The first step is formation of the enzyme-inhibitor tetrahedral intermediate with the inhibition constant (Ki), the second step is formation of the carbamyl enzyme with the carbamylation constant (kc), and the third step is hydrolysis of the carbamyl enzyme with decarbamylation constant (kd). According to pre-steady state kinetics the Ki step is divided further into two steps: (1) formation of the enzyme-inhibitor complex with the dissociation constant (KS) and (2) formation of the enzyme-inhibitor tetrahedral intermediate from the complex with the equilibrium constant (k2/k-2). Since the inhibitors are protonated in pH 7.0 buffer solution, the virtual dissociation constant (KS') of the enzyme-protonated inhibitor complex can be calculated from the equation, -log KS'=-log KS-pKa + 14. The -logKS, -log KS', log k2, and log k-2 values are multiply linearly correlated with the Jave equation (log(k/k0)=rho*sigma* + deltaEs + psi pi). For -log KS'-sigma*-Es)pi-correlation, the rho* value of -0.4 indicates that the enzyme-protonated inhibitor complexes have more positive charges than the protonated inhibitors, the delta value of 0.44 suggests that the bulkily substituted inhibitors lessen the reaction due to the difficulty of the inhibitors to enter the narrow enzyme active site gorge, and the psi value of 0.27 implies that the inhibitors with hydrophobic substituents accelerate the inhibitors entering the active site gorge of the enzyme. For log k2/k-2,-sigma*-Es-pi-correlation, the rho* value of 1.1 indicates that the enzyme-protonated inhibitor tetrahedral intermediates have more negative charges than the enzyme-protonated inhibitor complexes, the delta value of 0.15 suggests that the bulkily substituted inhibitors are difficult to bind into a small acyl binding site of the enzyme, and the psi value of -0.3 implies that the inhibitors with hydrophobic substituents resist binding to the hydrophilic acyl binding site of the enzyme.
Lin
Gialih
G
Department of Chemistry, National Chung-Hsing University, Taichung 402, Taiwan. gilin@dragon.nchu.edu.tw
Liao
Wei-Cheng
WC
Chan
Chung-Hwey
CH
Wu
Yi-Hian
YH
Tsai
Hou-Jen
HJ
Hsieh
Chi-Wei
CW
D000110:Acetylcholinesterase / Q000187:drug effects*; D002219:Carbamates / Q000737:chemistry* / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D007700:Kinetics; D021281:Quantitative Structure-Activity Relationship
D002219:Carbamates; D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase