Elucidating drug-metalloprotein interactions with tris(pyrazolyl)borate model complexes

The tetrahedral zinc complex [(Tp(Me,Ph))ZnOH] (Tp(Me,Ph) = hydrotris(5,3-methylphenylpyrazolyl)borate) was combined with acetohydroxamic acid, 3-mercapto-2-butanone, N-(methyl)mercaptoacetamide, beta-mercaptoethanol, 3-mercapto2-propanol, and 3-mercapto-2-butanol to generate the complexes [(Tp(Me,Ph))Zn(ZBG)] (ZBG = zinc-binding group). These complexes were prepared to determine the mode of binding for three different types of thiol-derived matrix metalloproteinase (MMP) inhibitors. The solid-state structures of all six metal complexes were determined by X-ray crystallography. The structures reveal that while beta-mercaptoketones and beta-mercaptoamides bind the zinc ion in a bidentate fashion, the three beta-mercaptoalcohol compounds only demonstrate monodentate coordination via the sulfur atom. Prior to this work, no experimental data were available for the binding conformation of these types of inhibitors to the zinc active site of MMPs. The results of these model studies reveal different binding modes for these ZBGs and are useful for explaining the results of inhibition assays and in second-generation drug design. This work demonstrates the utility of model complexes as a tool for revealing drug-metalloprotein interactions.