8CCG

The Fk1 domain of FKBP51 in complex with (2R,5S,12S)-12-(thiophen-2-yl)-2-[2-(3,4-dimethoxyphenyl)ethyl]-15,15-dimethyl-3,19-dioxa-10,13,16-triazatricyclo[18.3.1.0^5,^10]tetracosa-1(24),20,22-triene-4,11,14,17-tetrone

Summary for 8CCG

• Entry DOI: 10.2210/pdb8ccg/pdb
• Descriptor: Peptidyl-prolyl cis-trans isomerase FKBP5, (2~{R},5~{S},12~{S})-2-[2-(3,4-dimethoxyphenyl)ethyl]-15,15-dimethyl-12-thiophen-2-yl-3,19-dioxa-10,13,16-triazatricyclo[18.3.1.0^{5,10}]tetracosa-1(24),20,22-triene-4,11,14,17-tetrone (3 entities in total)
• Functional Keywords: fkbp51, safit, inhibitor, isomerase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 14667.81

Authors

Meyners, C.,Knaup, F.H.,Walz, C.M.,Hausch, F. (deposition date: 2023-01-27, release date: 2023-04-26, Last modification date: 2024-02-07)

Primary citation

Knaup, F.H.,Meyners, C.,Sugiarto, W.O.,Wedel, S.,Springer, M.,Walz, C.,Geiger, T.M.,Schmidt, M.,Sisignano, M.,Hausch, F.
Structure-Based Discovery of a New Selectivity-Enabling Motif for the FK506-Binding Protein 51.
J.Med.Chem., 66:5965-5980, 2023

PubMed Abstract: In recent years, the selective inhibition of FKBP51 has emerged as a possible treatment for chronic pain, obesity-induced diabetes, or depression. All currently known advanced FKBP51-selective inhibitors, including the widely used SAFit2, contain a cyclohexyl residue as a key motif for enabling selectivity over the closest homologue and anti-target FKBP52. During a structure-based SAR exploration, we surprisingly discovered thiophenes as highly efficient cyclohexyl replacement moieties that retain the strong selectivity of SAFit-type inhibitors for FKBP51 over FKBP52. Cocrystal structures revealed that the thiophene-containing moieties enable selectivity by stabilizing a flipped-out conformation of Phe of FKBP51. Our best compound, , potently binds to FKBP51 biochemically as well as in mammalian cells, desensitize TRPV1 in primary sensory neurons, and has an acceptable PK profile in mice, suggesting its use as a novel tool compound for studying FKBP51 in animal models of neuropathic pain.

PubMed: 37058391
DOI: 10.1021/acs.jmedchem.3c00249

Experimental method

X-RAY DIFFRACTION (1.3 Å)