New Beginnings for Matrix Metalloproteinase Inhibitors:  Identification of High-Affinity Zinc-Binding Groups

Abstract

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.

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“…Towards our goal to achieve selectivity we utilized the acquired scientific experience from the matrix metalloproteinases (MMPs) family of zinc endopeptidases, which has been intensively pursued during the last three decades. [18][19][20] Specifically, it has been demonstrated that employing strong zinc chelators, [21][22][23] 0960-894X/$ -see front matter Ó …”

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“…In particular, the catechol moiety of compound 6 appears to be the key functional region of the molecule as it chelates the Zn 2+ ion while aliphatic the five member ring fits nicely into an adjacent hydrophobic pocket (Figures 2A, C). The catechol functionality has been shown previously to be involved in the inhibition of various other metallo-proteases [18][19][20][21]. Interestingly, the hydroxyls groups are also predicted to be simultaneously involved in hydrogen bond interactions with the carboxylates of Glu 687 and Glu 375, side chains coordinating the metal ion (Figures 2A, C).…”