Lin_2012_Protein.Sci_21_1344

1,3,5-Tri-N-alkylcarbamylphloroglucinols 1-4 are synthesized as conformationally constrained analogs of triacylglycerols TGs to probe Jenck's proximity effect in the cholesterol esterase inhibition For the cholesterol esterase inhibition inhibitors 1-4 are 220-760-fold more potent than 1,2,3-tri-N-alkylcarbamylglycerols 13-15 that are substrate analogs of TG Comparison of tridentate inhibitors 1-4 bidentate inhibitors 3,5-di-N-n-alkylcarbamyloxyphenols 5-8 and monodentate inhibitors 5-N-n-alkylcarbamyloxyresorcinols 9-12 indicates that inhibitory potencies are as followed tridentate inhibitor bidentate inhibitor monodentate inhibitor The log k(i and pK(i values of tridentate inhibitors bidentate inhibitors and monodentate inhibitors are linearly correlated with the alkyl chain length indicating a common mechanism in each inhibition Also positive slopes of these correlations indicate that the longer chain inhibitors bind more tightly to the enzyme than the shorter ones Molecular dockings of tridentate 1 bidentate 5 and monodentate 9 into the X-ray crystal structure of cholesterol esterase suggest that one carbamyl group in the cis form of the inhibitor binds to the acyl chain-binding site of the enzyme The second carbamyl groups in the trans forms of inhibitors 1 and 5 bind to the second acyl chain-binding site of the enzyme The third carbamyl group in the trans form of inhibitor 1 binds to the third acyl chain-binding site of the enzyme Moreover the configuration of the inhibitor in the enzyme-inhibitor complex is the 1,3,5)-(cis trans trans)-tricarbamate form that mimics the gauche gauche)-conformation of TG.