9EU8
The FK1 domain of FKBP51 in complex with SAFit-analog 15h
This is a non-PDB format compatible entry.
Summary for 9EU8
| Entry DOI | 10.2210/pdb9eu8/pdb |
| Descriptor | Peptidyl-prolyl cis-trans isomerase FKBP5, (4-methyl-1,3-thiazol-5-yl)methyl (2S)-1-[(2S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)ethanoyl]piperidine-2-carboxylate (3 entities in total) |
| Functional Keywords | fkbp51, inhibitor, complex, isomerase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 29069.40 |
| Authors | Meyners, C.,Buffa, V.,Hausch, F. (deposition date: 2024-03-27, release date: 2024-06-12, Last modification date: 2024-09-11) |
| Primary citation | Buffa, V.,Meyners, C.,Sugiarto, W.O.,Bauder, M.,Gaali, S.,Hausch, F. 1,4-Pyrazolyl-Containing SAFit-Analogues are Selective FKBP51 Inhibitors With Improved Ligand Efficiency and Drug-Like Profile. Chemmedchem, 19:e202400264-e202400264, 2024 Cited by PubMed Abstract: The FK506 binding protein 51 (FKBP51) is an appealing drug target due to its role in several diseases such as depression, anxiety, chronic pain and obesity. Towards this, selectivity versus the close homolog FKBP52 is essential. However, currently available FKBP51-selective ligands such as SAFit2 are too large and lack drug-like properties. Here, we present a structure activity relationship (SAR) analysis of the pipecolic ester moiety of SAFit1 and SAFit2, which culminated in the discovery of the 1,4-pyrazolyl derivative 23 d, displaying a binding affinity of 0.077 μM for FKBP51, reduced molecular weight (541.7 g/mol), lower hydrophobicity (cLogP=3.72) and higher ligand efficiency (LE=0.25). Cocrystal structures revealed the importance of the 1,4- and 1,3,4- substitution patterns of the pyrazole ring versus the 1,4,5 arrangement. PubMed: 38818693DOI: 10.1002/cmdc.202400264 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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