UC San Diego

The use of bioinorganic tools for elucidating metal-ligand interactions has been examined. This thesis will first discuss the use of model complexes for the active site of the zinc(II)-dependent hydrolytic enzyme matrix metalloproteinases (MMP). Using these model complexes to understand how ligands bind the metal has helped in understanding the effects of pKa and hydrogen bonding on the binding mode of a variety of chelators. This binding mode can also be related to the potency of these groups as inhibitors of MMP-3. After discussing the use of zinc(II) model complexes, the use of cobalt(II) model complexes will be examined. Cobalt(II) model complexes are spectroscopic active analogs of the MMP active site. These model complexes were used to study the dynamics of these complexes in solution. These complexes have been studied by electronic absorption, X-ray diffraction, electron paramagnetic resonance and paramagnetic NMR to demonstrate how cobalt(II) complexes can be used as an alternative to protein crystallography to determine the binding mode of different ligands. After the study of cobalt(II) model complexes, the design of zinc(II) selective binding groups will be discussed. These nitrogen based groups preferentially bind zinc over iron. As well, synthesis of full length inhibitors based on these groups will be presented. These inhibitor studies have allowed a deeper understanding for how the binding groups orient in the active site of the MMP and reveal the best location for a backbone substituent. Finally, cellular studies of an inflammatory model will be discussed. This macrophage model contains five different metalloenzymes. In one experiment, the effect of each ligand on the activity of these metalloenzymes is analyzed. This allows us to understand some of the potential drawbacks and benefits of the metal binding groups utilized. As well, this method can be used as a screening tool for full length inhibitors of MMPfor full length inhibitors of MMPs