Structure–Affinity Relationship Analysis of Selective FKBP51 Ligands

The
FK506-binding protein 51 (FKBP51) is a promising drug target
for the treatment of stress-related psychiatric or metabolic disorders.
Just recently, the first selective ligands for FKBP51 were reported
based on an induced fit mechanism, but they are too large for a further
drug development process. We therefore designed and synthesized a
novel series of selective ligands to explore the requirements necessary
for binding to the induced-fit conformation. All ligands of this series
show no binding toward the structurally very similar antitarget FKBP52.
With the cocrystal structure of the best ligand in this novel series
we confirmed the induced fit mechanism. Furthermore, the structure–affinity
relationship provides information about beneficial structural features,
which is valuable for the development of improved FKBP51-directed
drugs.