5OAX

Galectin-3c in complex with thiogalactoside derivate

Summary for 5OAX

• Entry DOI: 10.2210/pdb5oax/pdb
• Related: 4BLI
• Descriptor: Galectin-3, 5,6-bis(fluoranyl)-3-[[(2~{S},3~{R},4~{S},5~{S},6~{R})-2-[(2~{S},3~{R},4~{S},5~{R},6~{R})-4-[4-(3-fluorophenyl)-1,2,3-triazol-1-yl]-6-(hydroxymethyl)-3,5-bis(oxidanyl)oxan-2-yl]sulfanyl-6-(hydroxymethyl)-3,5-bis(oxidanyl)oxan-4-yl]oxymethyl]chromen-2-one (3 entities in total)
• Functional Keywords: sugar binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 16432.76

Authors

Nilsson, U.J.,Peterson, K.,Hakansson, M.,Logan, D.T. (deposition date: 2017-06-25, release date: 2018-05-02, Last modification date: 2024-05-08)

Primary citation

Peterson, K.,Kumar, R.,Stenstrom, O.,Verma, P.,Verma, P.R.,Hakansson, M.,Kahl-Knutsson, B.,Zetterberg, F.,Leffler, H.,Akke, M.,Logan, D.T.,Nilsson, U.J.
Systematic Tuning of Fluoro-galectin-3 Interactions Provides Thiodigalactoside Derivatives with Single-Digit nM Affinity and High Selectivity.
J. Med. Chem., 61:1164-1175, 2018

PubMed Abstract: Symmetrical and asymmetrical fluorinated phenyltriazolyl-thiodigalactoside derivatives have been synthesized and evaluated as inhibitors of galectin-1 and galectin-3. Systematic tuning of the phenyltriazolyl-thiodigalactosides' fluoro-interactions with galectin-3 led to the discovery of inhibitors with exceptional affinities (K down to 1-2 nM) in symmetrically substituted thiodigalactosides as well as unsurpassed combination of high affinity (K 7.5 nM) and selectivity (46-fold) over galectin-1 for asymmetrical thiodigalactosides by carrying one trifluorphenyltriazole and one coumaryl moiety. Studies of the inhibitor-galectin complexes with isothermal titration calorimetry and X-ray crystallography revealed the importance of fluoro-amide interaction for affinity and for selectivity. Finally, the high affinity of the discovered inhibitors required two competitive titration assay tools to be developed: a new high affinity fluorescent probe for competitive fluorescent polarization and a competitive ligand optimal for analyzing high affinity galectin-3 inhibitors with competitive isothermal titration calorimetry.

PubMed: 29284090
DOI: 10.1021/acs.jmedchem.7b01626

Experimental method

X-RAY DIFFRACTION (1.2 Å)