Nuclear Magnetic Resonance Fragment-Based Identification of Novel FKBP12 Inhibitors

摘要

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 ris-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.