9QDB

The FK1 domain of FKBP51 in complex with the macrocyclic SAFit analog 29d

これはPDB形式変換不可エントリーです。

9QDB の概要

• エントリーDOI: 10.2210/pdb9qdb/pdb
• 分子名称: Peptidyl-prolyl cis-trans isomerase FKBP5, (2~{S},9~{S},12~{R})-2-cyclohexyl-20,23-dimethoxy-12-methyl-11,14,18-trioxa-4-azatricyclo[17.2.2.0^{4,9}]tricosa-1(22),19(23),20-triene-3,10-dione (3 entities in total)
• 機能のキーワード: inhibitor, complex, fkbp, 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: 29015.31

構造登録者

Meyners, C.,Brudy, C.,Hausch, F. (登録日: 2025-03-06, 公開日: 2025-12-03, 最終更新日: 2025-12-24)

主引用文献

Brudy, C.,Ruijsenaars, E.,Meyners, C.,Sugiarto, W.O.,Achaq, H.,Spiske, M.,Buffa, V.,Springer, M.,Repity, M.,Weller, A.,Haferkamp, U.,Pless, O.,Muschong, P.,Miltner, D.,Mezler, M.,Schmidt, M.V.,Riniker, S.,Hausch, F.
Linker Modification Enables Control of Key Functional Group Orientation in Macrocycles.
J.Med.Chem., 68:24890-24923, 2025

PubMed Abstract: Macrocycles are promising drug modalities that can enable unique ways of conformational preorganization, but how even minor modifications to a macrocyclic scaffold influence the conformational preorganization remains poorly understood. Here, we show how macrocyclization and further derivatization of the linker region can improve affinity, selectivity, and plasma stability in a highly atom-efficient manner. A single, solvent-exposed methyl group was found to improve binding affinity up to 10× over the nonmethylated analog. This led to highly ligand-efficient macrocycles with good brain permeability, improved solubility, and a promising in vivo profile for the FK506-binding protein 51 (FKBP51), a key regulator of the human stress response. Using high-resolution cocrystal structures and molecular dynamics simulations, we found that small linker variations can be tuned to shift the orientation of a key carbonyl group into an advantageous position. This effect is specific to macrocycles, highlighting their potential for fine-tuned adjustments to enable desired properties.

PubMed: 41273793
DOI: 10.1021/acs.jmedchem.5c00958

実験手法

X-RAY DIFFRACTION (2.05 Å)