Metalloenzymes are enzymes that utilize metal cofactors to catalyze chemical transformations. Such metals include, but are not limited to, Cu2+, Fe3+, Zn2+, and Mg2+. Overexpression or misregulation of metalloenzymes has been implicated in several diseases such as cancer, HIV, asthma and various bacterial infections. Consequently, there is a demand to develop novel and potent inhibitors for multiple metalloenzyme targets. In order to develop inhibitors, we utilized a fragment-based drug discovery (FBDD) approach wherein a ~250 metal-binding pharmacophore (MBP) library was utilized to identify hits against particular targets of interest. These MBPs can coordinate to the catalytic metal within an enzyme’s active site and serve as initial leads for inhibitor development. The focus of this project is to synthesize derivatives of MBPs, in an effort to develop full-length inhibitors.

Synthesis and evaluation of libraries of metalloenzyme inhibitors

251st National Meeting (2016)

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