Abstract
In an effort to identify promising non-hydroxamate inhibitors of matrix metalloproteinases (MMPs) several new zinc-binding groups (ZBGs) based on pyridine-derived or aza-macrocycle chelators have been examined. Fluorescence-based enzyme assays have been used to determine the IC50 values for these ZBGs against MMP-1, MMP-3, and anthrax lethal factor (LF). Many of these ligands were found to be remarkably potent, with IC50 values as much as 185-fold lower than that found for acetohydroxamic acid. These ligands are proposed to be more selective "warheads" for the inhibition of metalloenzymes that contain Zn2+ versus other metal ions at their active site.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Binding Sites
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Cations, Divalent
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Chelating Agents / chemistry
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Chelating Agents / pharmacology*
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Hydroxamic Acids / chemistry
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Hydroxamic Acids / pharmacology
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Kinetics
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Ligands
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Matrix Metalloproteinase Inhibitors*
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Matrix Metalloproteinases / chemistry
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Matrix Metalloproteinases / metabolism*
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Models, Molecular
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Protease Inhibitors / chemistry
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Protease Inhibitors / pharmacology*
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Zinc / chemistry
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Zinc / metabolism*
Substances
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Cations, Divalent
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Chelating Agents
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Hydroxamic Acids
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Ligands
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Matrix Metalloproteinase Inhibitors
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Protease Inhibitors
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acetohydroxamic acid
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Matrix Metalloproteinases
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Zinc