9FXZ

Galectin-8 N-terminal carbohydrate recognition domain in complex with 4-(bromophenyl)phthalazinone D-galactal ligand

「8CM8」から置き換えられました

9FXZ の概要

• エントリーDOI: 10.2210/pdb9fxz/pdb
• 分子名称: Galectin-8, 4-(4-bromophenyl)-2-[[(2~{R},3~{R},4~{R})-2-(hydroxymethyl)-3-oxidanyl-3,4-dihydro-2~{H}-pyran-4-yl]oxymethyl]phthalazin-1-one, CHLORIDE ION, ... (4 entities in total)
• 機能のキーワード: galectin, phthalazinone, inhibitor, sugar binding protein, immune system
• 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: 72662.14

構造登録者

Van Klaveren, S.,Hakansson, M.,Diehl, C.,Nilsson, N.J. (登録日: 2024-07-02, 公開日: 2025-07-16)

主引用文献

van Klaveren, S.,Hassan, M.,Hakansson, M.,Johnsson, R.E.,Larsson, J.,Jakopin, Z.,Anderluh, M.,Leffler, H.,Tomasic, T.,Nilsson, U.J.
Galectin-8N-Selective 4-Halophenylphthalazinone-Galactals Double pi-Stack in a Unique Pocket.
Acs Med.Chem.Lett., 15:1319-1324, 2024

PubMed Abstract: Galectin-8 contains two different carbohydrate recognition domains (CRDs). Selective inhibitors for at least one CRD are desirable for galectin-8 biology studies and potentially for pharmacological purposes. Structure-guided design led to the discovery of potent and selective glycomimetic-heterocycle hybrid ligands, with a 4-(-bromophenyl)phthalazinone derivative displaying a 34 μM for galectin-8N (N-terminal CRD), no binding to galectin-8C (C-terminal CRD), -1, -3, -4N, -7, -9C, or -9N, and >40-fold selectivity over galectin-4C. Selectivity was achieved with the halogenated 4-phenylphthalazinone moiety occupying a galectin-8N-specific sub-pocket. A 1.30 Å resolution X-ray structure revealed the phthalazinone moiety stacking with Arg45 and the 4-bromophenyl moiety stacking both Arg59 and Tyr141 of galectin-8N. Physicochemical and ADME studies revealed a desirable LogD, which also translated to good passive permeability. The chemical, microsome, and plasma stability support these compounds as promising tool compounds and candidates for hit-to-lead optimization.

PubMed: 39140038
DOI: 10.1021/acsmedchemlett.4c00212

実験手法

X-RAY DIFFRACTION (1.3 Å)