The DOI matches its OpenAlex record; 30 of the 30 references it cites were found in a registry or an index.
Kinetic basis for selective inhibition of cyclo-oxygenases
Open accessAbstract
Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the formation of prostaglandins by cyclo-oxygenases (COX). The discovery of a second COX isoform (COX-2) associated with inflammation led to agents that selectively inhibit COX-2, e.g. celecoxib. We evaluated the kinetics of inhibition of celecoxib and several NSAIDs. Celecoxib displays classic competitive kinetics on COX-1 (Ki=10-16 microM). An initial competitive interaction with COX-2 can also be discerned with celecoxib (Ki=11-15 microM), followed by a time-dependent interaction leading to potent inhibition, characterized as inactivation (Kinact=0.03-0.5 s-1). Half-maximal inhibition (IC50) using end-point assays reflects the competitive component on COX-1 (IC50=4-19 microM) and the inactivation component on COX-2 (IC50=0.003-0.006 microM). NSAIDs exhibit four distinct modes of COX inhibition based on kinetic behaviour: (1) competitive, e.g. ibuprofen; (2) weak binding, time-dependent, e.g. naproxen, oxicams; (3) tight binding, time-dependent, e.g. indomethacin; (4) covalent, e.g. aspirin. In addition, most NSAIDs display different kinetic behaviour for each isoform. Weakly binding inhibitors show variable behaviour in enzyme assays, with apparent inhibitory activity being markedly influenced by experimental conditions; determination of kinetic constants with this class is unreliable and IC50 values are strongly dependent on assay conditions. Although IC50 determinations are useful for structure/activity analyses, the complex and distinct mechanisms of enzyme inhibition of each COX isoform by the NSAIDs renders comparison of inhibitory activity on COX-1 and COX-2 using IC50 ratios of questionable validity.
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Cites
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Metadata
- Authors
- Gierse, J. K., Koboldt, C. M., Walker, M. C., Seibert, K., & Isakson, P. C.
- Venue
- Biochemical Journal
- Publisher
- Portland Press
- Published
- 1999-04-26
- Volume
- 339
- Issue
- 3
- Pages
- 607-607
- ISSN
- 0264-6021 (ISSN-L)
- OpenAlex
- W2090359132
- Cited by
- 287
- References
- 30
- FWCI
- 10.30
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Gierse, J. K., Koboldt, C. M., Walker, M. C., Seibert, K., & Isakson, P. C. (1999). Kinetic basis for selective inhibition of cyclo-oxygenases. Biochemical Journal. https://doi.org/10.1042/0264-6021%3A3390607
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
