Characterization of an exosite binding inhibitor of matrix metalloproteinase 13
| Autor: | Gregg B. Fields, Frank T. Coppo, Lusong Luo, Lata T. Gooljarsingh, Ami S. Lakdawala, Peter J. Tummino, Richard R. Gontarek |
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| Rok vydání: | 2007 |
| Předmět: |
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Molecular Pyrimidine Protein Conformation Stereochemistry Matrix metalloproteinase inhibitor Matrix Metalloproteinase Inhibitors Matrix metalloproteinase Biochemistry Article chemistry.chemical_compound Protein structure Matrix Metalloproteinase 13 medicine Protease Inhibitors Binding site Molecular Biology chemistry.chemical_classification Enzyme Precursors Binding Sites biology Chemistry Active site Tissue Inhibitor of Metalloproteinases Hydrogen-Ion Concentration Kinetics Enzyme biology.protein Marimastat medicine.drug |
| Zdroj: | Protein Science. 17:66-71 |
| ISSN: | 1469-896X 0961-8368 |
| DOI: | 10.1110/ps.073130208 |
| Popis: | Matrix metalloproteinase 13 (MMP13) is a key enzyme implicated in the degradation of the extracellular matrix in osteoarthritis. Clinical administration of broad spectrum MMP inhibitors such as marimastat has been implicated in severe musculo-skeletal side effects. Consequently, research has been focused on designing inhibitors that selectively inhibit MMP13, thereby circumventing musculo-skeletal toxicities. A series of pyrimidine dicarboxamides were recently shown to be highly selective inhibitors of MMP13 with a novel binding mode. We have applied a molecular ruler to this exosite by dual inhibition studies involving a potent dicarboxamide in the presence of two metal chelators of different sizes. A larger hydroxamate mimic overlaps and antagonizes binding of the dicarboxamide to the exosite whereas the much smaller acetohydroxamate synergizes with the dicarboxamide. These studies elucidate the steric requirement for compounds that fit exclusively into the active site, a mandate for generating highly selective MMP13 inhibitors. |
| Databáze: | OpenAIRE |
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