The purpose of this research is to develop novel inhibitors of the zinc-containing matrix metalloproteinases (MMPs) utilizing a bioinorganic approach. MMPs are implicated in numerous diseases such as cancer, arthritis, and inflammation. Inhibitors of MMPs consist of two """"""""domains"""""""": the zinc-binding group (ZBG) which chealtes the active site zinc and the inhibitor backbone which interacts with the active site residues. This research will focus first on the development of novel ZBGs. The design of ZBGs will involve three steps. First, a group of novel, ZBGs will be selected based on the known chemistry of zinc. Second, employing inorganic model complexes of MMPs, the binding modes, thermodynamics, and kinetics of binding of these ZBGs will be compared to known ZBGs. Once the most superior ZBGs have been identified, their in vitro inhibitory efficacy will be tested in MMP assays. These steps will provide a simple yet effective method for an initial screening of novel ZBGs. The design of the inhibitor backbones will be initiated using a computational approach to identify the optimal backbones for specific locations in the active site. The two components (ZBG and backbone) will be combined to create potent, novel MMP inhibitors. ? ?
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