Novel cyclooxygenase-1 inhibitors discovered using affinity fingerprints
| Autor: | Reyna J. Simon, Komath Damodaran, Thomas J. Macke, Reinaldo F. Gomez, Edgardo Laborde, Hugo O. Villar, James G. Keck, Steven R. Schow, Nancy Hsu, Lum Robert T, Danying Cai, Michael M. Wick, Graeme R. Martin, Paul Beroza |
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| Rok vydání: | 2004 |
| Předmět: |
Models
Molecular Drug Evaluation Preclinical Quantitative Structure-Activity Relationship Ibuprofen Inhibitory Concentration 50 Drug Discovery Combinatorial Chemistry Techniques Cyclooxygenase Inhibitors Prospective Studies chemistry.chemical_classification biology Molecular Structure Chemistry Anti-Inflammatory Agents Non-Steroidal Models Theoretical Combinatorial chemistry Isoenzymes Enzyme Biochemistry Enzyme inhibitor Prostaglandin-Endoperoxide Synthases Drug Design biology.protein Cyclooxygenase 1 Molecular Medicine Cyclooxygenase |
| Zdroj: | Journal of medicinal chemistry. 47(20) |
| ISSN: | 0022-2623 |
| Popis: | We used protein affinity fingerprints to discover structurally novel inhibitors of cyclooxygenase-1 (COX-1) by screening a selected number of compounds, thus providing an alternative to extensive screening. From the affinity fingerprints of 19 known COX-1 inhibitors, a computational model for COX-1 inhibition was constructed and used to select candidate inhibitors from our compound library to be tested in the COX-1 assay. Subsequent refinement of the model by including affinity fingerprints of inactive compounds identified three molecules that were more potent than ibuprofen, a commonly used COX-1 inhibitor. These compounds are structurally distinct from those used to build the model and were discovered by testing only 62 library compounds. The discovery of these leads demonstrates the efficiency with which affinity fingerprints can identify novel bioactive chemotypes from known drugs. |
| Databáze: | OpenAIRE |
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