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Characterization of an exosite binding inhibitor of matrix metalloproteinase 13
Lata T Gooljarsingh1, Ami Lakdawala, Frank Coppo
1Department of Enzymology and Mechanistic Pharmacology, GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania 19426, USA. gooljat@wyeth.com
Abstract:
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.
Insights
Researchers developed selective MMP13 inhibitors for osteoarthritis, avoiding side effects of broad-spectrum drugs. Dual inhibition studies revealed steric requirements for potent and selective MMP13 targeting.
Area of Science:
- Biochemistry
- Pharmacology
- Drug Discovery
Background:
- Matrix metalloproteinase 13 (MMP13) drives extracellular matrix degradation in osteoarthritis.
- Broad-spectrum MMP inhibitors cause severe musculoskeletal toxicity, necessitating selective MMP13 inhibitors.
Purpose of the Study:
- To investigate the binding exosite of MMP13 using a molecular ruler approach.
- To elucidate steric requirements for developing highly selective MMP13 inhibitors.
Main Methods:
- Dual inhibition studies using a pyrimidine dicarboxamide and metal chelators of varying sizes (acetohydroxamate, larger hydroxamate mimic).
- Analysis of competitive and synergistic binding interactions at the MMP13 exosite.
Main Results:
- A larger hydroxamate mimic antagonized dicarboxamide binding, indicating steric hindrance.
- Smaller acetohydroxamate synergized with the dicarboxamide, suggesting complementary binding.
- These findings define specific steric constraints for exclusive active site occupation.
Conclusions:
- The study elucidates critical steric requirements for selective MMP13 inhibition.
- Findings guide the design of next-generation MMP13 inhibitors to mitigate osteoarthritis progression and associated toxicities.
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