Using Model Complexes To Augment and Advance Metalloproteinase Inhibitor Design

The tetrahedral zinc complex [(TpPh,Me)ZnOH] (TpPh,Me = hydrotris(3,5-phenylmethylpyrazolyl)borate) was combined
with 2-thenylmercaptan, ethyl 4,4,4-trifluoroacetoacetate, salicylic acid, salicylamide, thiosalicylic acid, thiosalicylamide,
methyl salicylate, methyl thiosalicyliate, and 2-hydroxyacetophenone to form the corresponding [(TpPh,Me)Zn(ZBG)]
complexes (ZBG = zinc-binding group). X-ray crystal structures of these complexes were obtained to determine
the mode of binding for each ZBG, several of which had been previously studied with SAR by NMR (structure−activity relationship by nuclear magnetic resonance) as potential ligands for use in matrix metalloproteinase inhibitors.
The [(TpPh,Me)Zn(ZBG)] complexes show that hydrogen bonding and donor atom acidity have a pronounced effect
on the mode of binding for this series of ligands. The results of these studies give valuable insight into how ligand
protonation state and intramolecular hydrogen bonds can influence the coordination mode of metal-binding proteinase
inhibitors. The findings here suggest that model-based approaches can be used to augment drug discovery methods
applied to metalloproteins and can aid second-generation drug design.