A fragment library consisting of metal-binding pharmacophores (MBPs) has been designed and employed in inhibition studies of medicinally relevant metalloenzymes. A second library of compounds has been combined with an earlier reported1 96 component chelator fragment library (CFL-1.1). This expanded library has been screened at micromolar concentrations (200-500 �M) against metalloenzyme targets, and hits from these screens are being elaborated to produce more potent inhibitory molecules by fragment-based lead discovery (FBLD). Enzymes evaluated include carbonic anhydrase, several matrix metalloproteases, histone deacetylases, HIV integrase, and influenza endonuclease. Even at fragment concentrations as low as 200 �M, this library produced hit rates >10%, with fragments exhibiting IC50values as low as 2 �M. Current efforts involve the expansion of this library to include more chemically diverse MBPs and screenings against other relevant metalloenzymes, as well as lead-expansion to full length inhibitors with potential use as pharmaceuticals.1. Jacobsen, J. A.; Fullagar, J. L.; Miller, M. T.; Cohen, S. M., Identifying Chelators for Metalloprotein Inhibitors Using a Fragment-Based Approach. Journal of Medicinal Chemistry 2011,  54 (2), 591-602.

Chelating-fragment libraries as a tool in novel metalloenzyme inhibitor discovery

248th National Meeting (2014)

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