5DIV

The Fk1 domain of FKBP51 in complex with the new synthetic ligand (S)-N-(1-carbamoylcyclopentyl)-1-((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxamide

Summary for 5DIV

• Entry DOI: 10.2210/pdb5div/pdb
• Descriptor: Peptidyl-prolyl cis-trans isomerase FKBP5, (2S)-N-(1-carbamoylcyclopentyl)-1-[(2S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl]piperidine-2-carboxamide (3 entities in total)
• Functional Keywords: fk-506 binding domain, hsp90 cochaperone, immunophiline, peptidyl-prolyl isomerase, ligand selectivity, isomerase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: Q13451
• Total number of polymer chains: 1
• Total formula weight: 14426.63

Authors

Gaali, S.,Feng, X.,Sippel, C.,Bracher, A.,Hausch, F. (deposition date: 2015-09-01, release date: 2016-03-23, Last modification date: 2024-05-08)

Primary citation

Gaali, S.,Feng, X.,Hahle, A.,Sippel, C.,Bracher, A.,Hausch, F.
Rapid, Structure-Based Exploration of Pipecolic Acid Amides as Novel Selective Antagonists of the FK506-Binding Protein 51.
J.Med.Chem., 59:2410-2422, 2016

PubMed Abstract: The FK506-binding protein 51 (FKBP51) is a key regulator of stress hormone receptors and an established risk factor for stress-related disorders. Drug development for FKBP51 has been impaired by the structurally similar but functionally opposing homologue FKBP52. High selectivity between FKBP51 and FKBP52 can be achieved by ligands that stabilize a recently discovered FKBP51-favoring conformation. However, drug-like parameters for these ligands remained unfavorable. In the present study, we replaced the potentially labile pipecolic ester group of previous FKBP51 ligands by various low molecular weight amides. This resulted in the first series of pipecolic acid amides, which had much lower molecular weights without affecting FKBP51 selectivity. We discovered a geminally substituted cyclopentyl amide as a preferred FKBP51-binding motif and elucidated its binding mode to provide a new lead structure for future drug optimization.

PubMed: 26954324
DOI: 10.1021/acs.jmedchem.5b01355

Experimental method

X-RAY DIFFRACTION (1.65 Å)