Molecular pharmacological interaction of phenylbutazone to human neutrophil elastase.
- Author:
Kooil KANG
1
Author Information
1. Department of Pharmacology, Kosin University Medical College, Pusan 602-702, Korea.
- Publication Type:Original Article
- Keywords:
Neutrophil elastase;
Molecular modeling;
Phenylbutazone;
Inhibition of elastase
- MeSH:
Amino Acids;
Catalytic Domain;
Chromatography, Gel;
Chromatography, Ion Exchange;
Humans*;
Hydrophobic and Hydrophilic Interactions;
Leukocyte Elastase*;
Masks;
Models, Molecular;
Neutrophils*;
Pancreatic Elastase;
Phenylbutazone*
- From:The Korean Journal of Physiology and Pharmacology
1998;2(3):385-393
- CountryRepublic of Korea
- Language:English
-
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.
