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|標題:||Ortho effects in quantitative structure activity relationships for lipase inhibition by aryl carbamates||作者:||Lin, G.L.
|關鍵字:||QSAR;ortho effects;cross-interactions;lipase inhibition;carbamate;inhibitors;structure-reactivity relationships;pancreatic cholesterol esterase;open conformation;binding site;mechanism;probes||Project:||Qsar & Combinatorial Science||期刊/報告no：:||Qsar & Combinatorial Science, Volume 22, Issue 8, Page(s) 852-858.||摘要:||
Ortho-substituted phenyl-N-butyl carbamates (1-11) are synthesized and evaluated for their inhibition effects on Pseudomonas species lipase. Carbamates 1-11 are characterized as pseudo-substrate inhibitors of the enzyme. The logarithms of dissociation constant (K-i), carbamylation constant (k(2)), and bimolecular inhibition constant (k(i)) multiply linearly correlate with Hammett substituent constant (sigma), Taft-Kutter-Hansch ortho steric constant (E-S), and Swan-Lupton field constant (F). For - logK(i)-, logk(2)-, and logk(i)-correlations, values of rho, delta, f rho(XR) are 0.2, -0.06, -1.7, 0.8; 0.0, 0.0, 1.0, -0.07; and -1.8, 7, 0.6, 5; respectively. The enzyme inhibition mechanism is composed of four steps: 1) the first step which is protonation of carbamates 1 - 11, 2) the second step (Ki,) which involves in the proton 1,3-shift of protonated carbamates 1-11 then the pseudo-trans to cis conformational change, 3) the third step (K-i2) which is formation of a negative charged enzyme-inhibitor tetrahedral intermediate, and 4) the fourth step (k(2)) which is the carbamylation step. The former three steps are likely composed of the K-i step. There is little ortho steric enhancement effect in the K-i step. From cross-interaction correlations, distance between carbamate and phenyl substituents in transition state for the K-i step is relatively short due to a large rho(XR) value of 7. The k(2) step is insensitive to ortho steric effect. The k(2) step involves in departure of leaving group, substituted phenol in which is protonated from the proton 1,3-shift but not from the active site histidine of the enzyme. From cross-interaction correlations, the distance between carbamate and phenyl substituents in transition state for the k(2) step is relatively long due to a small rho(XR) value of 0.6.
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