8OJK

Galectin-3 in complex with 2,6-anhydro-3-deoxy-3-S-(beta-D-galactopyranosyl)-3-thio-D-glycero-L-altro-heptonamide

8OJK の概要

• エントリーDOI: 10.2210/pdb8ojk/pdb
• 分子名称: Galectin-3, 1-thio-beta-D-galactopyranose, (2~{R},4~{R},5~{R},6~{R})-6-(hydroxymethyl)-4,5-bis(oxidanyl)oxane-2-carboxamide, ... (5 entities in total)
• 機能のキーワード: sugar binding protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 16112.76

構造登録者

Tsagkarakou, A.S.,Leonidas, D.D. (登録日: 2023-03-24, 公開日: 2023-09-13, 最終更新日: 2023-09-20)

主引用文献

Lazar, L.,Tsagkarakou, A.S.,Stravodimos, G.,Kontopidis, G.,Leffler, H.,Nilsson, U.J.,Somsak, L.,Leonidas, D.D.
Strong Binding of C -Glycosylic1,2-Thiodisaccharides to Galectin-3─Enthalpy-Driven Affinity Enhancement by Water-Mediated Hydrogen Bonds.
J.Med.Chem., 66:12420-12431, 2023

PubMed Abstract: Galectin-3 is involved in multiple pathways of many diseases, including cancer, fibrosis, and diabetes, and it is a validated pharmaceutical target for the development of novel therapeutic agents to address unmet medical needs. Novel 1,2-thiodisaccharides with a -glycosylic functionality were synthesized by the photoinitiated thiol-ene click reaction of -peracylated 1-C-substituted glycals and 1-thio-glycopyranoses. Subsequent global deprotection yielded test compounds, which were studied for their binding to human galectin-3 by fluorescence polarization and isothermal titration calorimetry to show low micromolar values. The best inhibitor displayed a value of 8.0 μM. An analysis of the thermodynamic binding parameters revealed that the binding Gibbs free energy (Δ) of the new inhibitors was dominated by enthalpy (Δ). The binding mode of the four most efficient 1,2-thiodisaccharides was also studied by X-ray crystallography that uncovered the unique role of water-mediated hydrogen bonds in conferring enthalpy-driven affinity enhancement for the new inhibitors. This 1,2-thiodisaccharide-type scaffold represents a new lead for galectin-3 inhibitor discovery and offers several possibilities for further development.

PubMed: 37658813
DOI: 10.1021/acs.jmedchem.3c00882

実験手法

X-RAY DIFFRACTION (1.8 Å)