Korean J Physiol Pharmacol.  1998 Jun;2(3):385-393.

Molecular pharmacological interaction of phenylbutazone to human neutrophil elastase

• Kang K

Abstract

Human neutrophil elastase (HNElastase, EC 3.4.21.37), a causative factor of inflammatory diseases, was purified by Ultrogel AcA54 gel filtration and CM-Sephadex ion exchange chromatography. HNElastase was inhibited by phenylbutazone in a concentration dependent manner up to 0.4 mm, but as the concentration increased, the inhibitory effect gradually diminished. Binding of phenylbutazone to the human neutrophil elastase caused strong Raman shifts at 200, 440, and 1194 cm-1. The peak at 1194 cm-1 might be evidence of the presence of -N=N-PHI radical. The core area of the elastase, according to the visual molecular model of human neutrophil elastase, was structurally stable. A deeply situated active center was at the core area surrounded by hydrophobic amino acids. Directly neighboring the active site was one positively charged atom and two atoms carrying a negative charge, which enabled the enzyme and the drug to form a strong interaction. Phenylbutazone may form a binding, similar to a key & lock system to the atoms carrying opposite charges near the active site of the enzyme molecule. Furthermore, the hydrophobicity of the surrounding amino acid near the active site seemed to enhance the binding strength of phenylbutazone. Binding of phenylbutazone near the active site may cause masking of the active site, preventing the substrate from approaching the active site and inhibiting elastase activity.

Keyword

Neutrophil elastase; Molecular modeling; Phenylbutazone; Inhibition of elastase

MeSH Terms

Amino Acids
Catalytic Domain
Chromatography, Gel
Chromatography, Ion Exchange
Humans*
Hydrophobic and Hydrophilic Interactions
Leukocyte Elastase*
Masks
Models, Molecular
Neutrophils*
Pancreatic Elastase
Phenylbutazone*
Amino Acids
Leukocyte Elastase
Pancreatic Elastase
Phenylbutazone