7P1M

Galectin-8 N-terminal carbohydrate recognition domain in complex with benzimidazole D-galactal ligand

Summary for 7P1M

• Entry DOI: 10.2210/pdb7p1m/pdb
• Descriptor: Galectin-8, 2-[[(2R,3R,4R)-2-(hydroxymethyl)-3-oxidanyl-3,4-dihydro-2H-pyran-4-yl]oxymethyl]-3-methyl-benzimidazole-5-carboxylic acid, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: inhibitor, complex, galectin, lectin, d-galactal, sugar binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 34867.25

Authors

Hassan, M.,Hakansson, M.,Nilsson, J.U.,Kovacic, R. (deposition date: 2021-07-02, release date: 2021-12-15, Last modification date: 2024-01-31)

Primary citation

Hassan, M.,Baussiere, F.,Guzelj, S.,Sundin, A.P.,Hakansson, M.,Kovacic, R.,Leffler, H.,Tomasic, T.,Anderluh, M.,Jakopin, Z.,Nilsson, U.J.
Structure-Guided Design of d-Galactal Derivatives with High Affinity and Selectivity for the Galectin-8 N-Terminal Domain.
Acs Med.Chem.Lett., 12:1745-1752, 2021

PubMed Abstract: Galectin-8 is a carbohydrate-binding protein that plays a crucial role in tumor progression and metastasis, antibacterial autophagy, modulation of the immune system, and bone remodeling. The design, synthesis, and protein affinity evaluation of a set of C-3 substituted benzimidazole and quinoline d-galactal derivatives identified a d-galactal-benzimidazole hybrid as a selective ligand for the galectin-8 N-terminal domain (galectin-8N), with a of 48 μM and 15-fold selectivity over galectin-3 and even better selectivity over the other mammalian galectins. X-ray structural analysis of galectin-8N in complex with one benzimidazole- and one quinoline-galactal derivative at 1.52 and 2.1 Å together with molecular dynamics simulations and quantum mechanical calculations of galectin-8N in complex with the benzimidazole derivative revealed orbital overlap between a NH LUMO of Arg45 with electron rich HOMOs of the olefin and O4 of the d-galactal. Such overlap is hypothesized to contribute to the high affinity of the d-galactal-derived ligands for galectin-8N. A (3-(4,5-dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4-sulfophenyl)-2-tetrazolium) (MTS) assay evaluation of the d-galactal-benzimidazole hybrid and an analogous galactoside derivative on a panel of cell lines with MTS assay showed no effect on cell viability up to 100 μM concentration. A subsequent functional assay using the MDA-MB-231 cell line demonstrated that the d-galactal-benzimidazole hybrid and the analogous galactoside derivative reduced the secretion of the proinflammatory cytokines interleukin-6 (IL-6) and IL-8 in a dose-dependent manner. Therefore, these compounds represent potential probes for galectin-8N pharmacology investigations and possibly promising leads for the design and synthesis of potent and selective galectin-8 inhibitors as potential antitumor and anti-inflammatory agents.

PubMed: 34795863
DOI: 10.1021/acsmedchemlett.1c00371

Experimental method

X-RAY DIFFRACTION (1.52 Å)