9EUB

The FK1 domain of FKBP51 in complex with SAFit-analog 24e

これはPDB形式変換不可エントリーです。

9EUB の概要

• エントリーDOI: 10.2210/pdb9eub/pdb
• 分子名称: Peptidyl-prolyl cis-trans isomerase FKBP5, [1-(2-hydroxyethyl)pyrazol-4-yl]methyl (2S)-1-[(2S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)ethanoyl]piperidine-2-carboxylate (3 entities in total)
• 機能のキーワード: fkbp51, inhibitor, complex, isomerase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 29095.36

構造登録者

Meyners, C.,Buffa, V.,Hausch, F. (登録日: 2024-03-27, 公開日: 2024-06-12, 最終更新日: 2024-09-11)

主引用文献

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

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: 38818693
DOI: 10.1002/cmdc.202400264

実験手法

X-RAY DIFFRACTION (2 Å)