Structural highlights
Function
[FKBP5_HUMAN] Interacts with functionally mature heterooligomeric progesterone receptor complexes along with HSP90 and TEBP.
Publication Abstract from PubMed
The FK506-binding protein 51 (FKBP51) emerged as a key player in several diseases like stress-related disorders, chronic pain, and obesity. Linear analogues of FK506 called SAFit were shown to be highly selective for FKBP51 over its closest homologue FKBP52, allowing the proof-of-concept studies in animal models. Here, we designed and synthesized the first macrocyclic FKBP51-selective ligands to stabilize the active conformation. All macrocycles retained full FKBP51 affinity and selectivity over FKBP52 and the incorporation of polar functionalities further enhanced affinity. Six high-resolution crystal structures of macrocyclic inhibitors in complex with FKBP51 confirmed the desired selectivity-enabling binding mode. Our results show that macrocyclization is a viable strategy to target the shallow FKBP51 binding site selectively.
Structure-Based Design of High-Affinity Macrocyclic FKBP51 Inhibitors.,Bauder M, Meyners C, Purder PL, Merz S, Sugiarto WO, Voll AM, Heymann T, Hausch F J Med Chem. 2021 Mar 5. doi: 10.1021/acs.jmedchem.0c02195. PMID:33666419[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Bauder M, Meyners C, Purder PL, Merz S, Sugiarto WO, Voll AM, Heymann T, Hausch F. Structure-Based Design of High-Affinity Macrocyclic FKBP51 Inhibitors. J Med Chem. 2021 Mar 5. doi: 10.1021/acs.jmedchem.0c02195. PMID:33666419 doi:http://dx.doi.org/10.1021/acs.jmedchem.0c02195
