Metalloenzymes are responsible for a wide range of biological functions, and their misregulation has been implicated in many illnesses such as heart disease, inflammation, and pathogenic virulence. Despite decades of research, metalloprotein inhibitors are still very challenging to design and develop. Many inhibitors still use a hydroxamate functionality to bind the catalytic metal and only minimal efforts have been performed to develop inhibitors that contain different metal binding groups (MBGs). This research presentation focuses on determining what factors affect the affinity of MBGs for different proteins by comparing their inhibitory activity, thermodynamics of binding, and coordination geometry. Inhibitory data against carbonic anhydrase will be presented for a large number of MBGs. For molecules that show high activity, detailed analysis including isothermal titration calorimetry and x-ray crystallography will be presented.

Identifying optimal chelators for metalloprotein inhibitors

243rd National Meeting (2012)

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