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At least 127 records · Page 7Linked to original sources
PubMed1990

Thermodynamic cycle-perturbation study of the binding of trifluoroacetyl dipeptide anilide inhibitors with porcine pancreatic elastase.

The variety of results of crystallographic studies of the serine proteases complexed with isocoumarin inhibitors presents a challenging problem to modeling methods and molecular energetics. Therefore, the thermodynamic cycle-perturbation technique has been used to study a model system of elastase and two peptidic inhibitors. Using the program AMBER, the technique correctly predicts changes of the binding constants for the trifluoroacetyl dipeptide inhibitors in comparison with available experimental (kinetic and crystallographic) data. However, the absolute values obtained are shown to be sensitive to the specific electrostatic interaction potential parameters used in the simulations. The reader and user are cautioned that thermodynamic cycle-perturbation results may be too optimistic by underestimating the accuracy of free energy values. This is especially a matter of concern for those cases where a direct comparison with experimental values is not possible, viz., (1) the stimulation of binding of novel compounds, (2) structurally uncertain binding sites, or (3) structurally different binding modes. With our best 4-31G* ESP (electrostatic potential) charges we were able to reproduce experimentally determined free energy differences (delta delta A) with an accuracy of about 1.5 kcal/mol. Dynamically induced structural changes in the binding site of elastase, and particularly changes in hydrogen-bond patterns of the binding site, are also reported.

Anilides↗
PubMed1987

Cryoenzymology of human plasmin catalysis: comparison of cryosolvents and reactions with nitrophenyl ester and anilide substrates.

A comparative study of nucleophilic (methanol), aprotic (dimethyl sulfoxide), and protic but non nucleophilic (ethylene glycol, ethylene glycol/dimethylformamide) solvents on the catalytic and structural properties of human plasmin has been made. All four solvent systems are potentially suitable as cryosolvents for plasmin catalysis at subzero temperatures although the solubility of plasmin is limited in the methanol and dimethyl sulfoxide systems. Each cryosolvent system caused minor effects on the catalytic properties of the enzyme, which could be rationalized in terms of the known physical properties of the cosolvent. Solvent systems containing ethylene glycol induce a minor conformational change which increases the catalytic efficiency of plasmin. The cosolvent effects on Km and Ki indicate that electrostatic interactions dominate the binding of both substrates and inhibitors such as benzamidine. A change in slope of the Arrhenius plots for catalysis, reflecting a temperature-induced isomerization, is observed around 0 degree C; the energies of activation being 13 +/- 2 kcal mol-1 at higher temperatures and 19 +/- 2 kcal mol-1 at subzero temperatures, and essentially independent of solvent. Deacylation was shown to be the rate-limiting step in the hydrolysis of specific p-nitrophenyl ester substrates. Previous stopped-flow studies at room temperature provided observations suggesting that a tetrahedral intermediate could be detected in the plasmin-catalyzed hydrolysis of p-nitroanilide substrates. Experiments at subzero temperatures with such substrates failed to reveal any buildup of a tetrahedral intermediate under the experimental conditions.

Anilides↗