New beginnings for matrix metalloproteinase inhibitors: identification of high-affinity zinc-binding groups.
In an effort to identify promising non-hydroxamate inhibitors of matrix metalloproteinases (MMPs), several new zinc-binding groups (ZBGs) based on pyrone, pyrothione, hydroxypyridinone, and hydroxypyridinethione chelators have been examined. Structural studies with tris(pyrazolyl)borate model complexes show that these ligands bind to the MMP active site zinc(II) ion in a bidentate fashion, similar to that found with hydroxamate-based inhibitors. Fluorescence- and colorimetric-based enzyme assays have been used to determine the IC50 values for these ZBGs against MMP-3; mixed O,S-donor ligands were found to be remarkably potent, with IC50 values as much as 700-fold lower than that found for acetohydroxamic acid. Inhibitory activity was found to parallel metal binding affinity as determined in titrations with model complexes. These results demonstrate that MPIs based on new ZBGs are feasible and may indeed improve the overall performance of inhibitors designed against these important medicinal targets.
Puerta
David T
DT
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, USA.
Lewis
Jana A
JA
Cohen
Seth M
SM
D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D019278:Matrix Metalloproteinase 3 / Q000737:chemistry / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000737:chemistry / Q000378:metabolism; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D011753:Pyrones / Q000737:chemistry / Q000494:pharmacology; D013050:Spectrometry, Fluorescence; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000494:pharmacology; D015032:Zinc / Q000737:chemistry* / Q000378:metabolism
D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D011725:Pyridines; D011753:Pyrones; D013438:Sulfhydryl Compounds; D020782:Matrix Metalloproteinases; D019278:Matrix Metalloproteinase 3; D015032:Zinc