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Inhibition of cathepsin G by 2-amino-3,1-benzoxazin-4-ones: kinetic investigations and docking studies. | LitMetric

AI Article Synopsis

  • A study investigated how human cathepsin G interacts with various acyl-enzyme inhibitors, focusing on the impact of different residues at a specific position of the inhibitors.
  • Slow-binding kinetics were used to gather data on the enzyme's acylation and deacylation processes, allowing researchers to determine critical steps in these reactions.
  • Docking simulations revealed how certain inhibitors bind to the active site of the enzyme, with variations in orientation affecting the binding efficacy and interaction strength.

Article Abstract

A series of benzoxazinones was used to investigate the interaction of human cathepsin G with acyl-enzyme inhibitors. With respect to the primary specificity of cathepsin G, inhibitors with hydrophobic or basic residues at position 2 were included in the study. Parameters of the enzyme acylation and deacylation were determined by slow-binding kinetics in the presence of a chromogenic substrate. For selected inhibitors, the time course of the enzyme-catalyzed conversion of the inhibitors was followed. This approach was suitable to elucidate a rate-determining deacylation step. Docking simulations of the noncovalent enzyme-inhibitor complexes were performed and several clusters were analyzed for each inhibitor. The amino acids of the active site that participate in the binding of the inhibitors were determined. The arrangements in several clusters of an inhibitor were not uniform with respect to the orientation by which the inhibitor was bound in the S(1) pocket. Docking of the basic piperazino derivatives 6 and 10 indicated an interaction with Glu 226 at the bottom of the S(1) specificity pocket. The (N-methyl)benzylamino derivative 1 showed the strongest acylation rate (k(on)=1200 M(-1) s(-1)), which was attributed to a high extent of pseudo-productive orientations of the noncovalent preassociation complex.

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http://dx.doi.org/10.1016/S0003-9861(02)00054-1DOI Listing

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