Nuclear Magnetic Resonance Fragment-Based Identification of Novel FKBP12 Inhibitors

Peptidyl−prolyl cis–trans isomerases are a group of cytosolic enzymes initially characterized by their ability to catalyze the cis–trans isomerization of peptidyl−prolyl bonds. This represents a significant event for protein folding because cis-proline introduces critical bends within the protein conformation. FK506-binding proteins (FKBPs) represent one of the three families of enzymes sharing peptidyl−prolyl cis−trans isomerase activity. Inhibitors of FKBP12, in particular, have potent neurotrophic properties both in vivo and in vitro. Here, we describe a fragment-based unbiased nuclear magnetic resonance drug discovery approach for the identification of novel classes of chemical inhibitors against FKBP12. Compared to FK506, the fragment-based FKBP12 inhibitors developed herein possess significant advantages as drug candidates.