Selective inhibitors of the FK506-binding protein 51 by induced fit

Nat Chem Biol. 2015 Jan;11(1):33-7. doi: 10.1038/nchembio.1699. Epub 2014 Dec 1.


The FK506-binding protein 51 (FKBP51, encoded by the FKBP5 gene) is an established risk factor for stress-related psychiatric disorders such as major depression. Drug discovery for FKBP51 has been hampered by the inability to pharmacologically differentiate against the structurally similar but functional opposing homolog FKBP52, and all known FKBP ligands are unselective. Here, we report the discovery of the potent and highly selective inhibitors of FKBP51, SAFit1 and SAFit2. This new class of ligands achieves selectivity for FKBP51 by an induced-fit mechanism that is much less favorable for FKBP52. By using these ligands, we demonstrate that selective inhibition of FKBP51 enhances neurite elongation in neuronal cultures and improves neuroendocrine feedback and stress-coping behavior in mice. Our findings provide the structural and functional basis for the development of mechanistically new antidepressants.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Psychological / drug effects
  • Animals
  • Antidepressive Agents / pharmacology
  • Behavior, Animal / drug effects
  • Binding Sites / drug effects
  • Cells, Cultured
  • Drug Discovery
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutation / genetics
  • Neurites / drug effects
  • Protein Conformation
  • Tacrolimus Binding Proteins / antagonists & inhibitors*
  • Tacrolimus Binding Proteins / chemistry
  • Tacrolimus Binding Proteins / drug effects


  • Antidepressive Agents
  • Tacrolimus Binding Proteins
  • tacrolimus binding protein 4
  • tacrolimus binding protein 5

Associated data

  • PDB/4TW6
  • PDB/4TW7
  • PDB/4TW8