8ILU

Crystal structure of mouse Galectin-3 in complex with small molecule inhibitor

Summary for 8ILU

• Entry DOI: 10.2210/pdb8ilu/pdb
• Descriptor: Galectin-3, (2R,3R,4R,5R,6S)-2-(hydroxymethyl)-6-[2-(2-methyl-1,3-benzothiazol-6-yl)-1,2,4-triazol-3-yl]-4-[4-[3,4,5-tris(fluoranyl)phenyl]-1,2,3-triazol-1-yl]oxane-3,5-diol, THIOCYANATE ION, ... (5 entities in total)
• Functional Keywords: fibrosis, galactose, sugar binding protein
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 2
• Total formula weight: 34109.92

Authors

Kumar, A.,Jinal, S.,Raman, S.,Ghosh, K. (deposition date: 2023-03-04, release date: 2024-03-06, Last modification date: 2024-09-25)

Primary citation

Liu, C.,Wang, W.,Feng, J.,Beno, B.,Raja, T.,Swidorski, J.,Manepalli, R.K.V.L.P.,Vetrichelvan, M.,Rao Jalagam, P.,Nair, S.K.,Gupta, A.,Panda, M.,Ghosh, K.,Kaushikkumar Shukla, J.,Sale, H.,Shah, D.,Singh Gautam, S.,Patel, D.,Mathur, A.,Ellsworth, B.A.,Cheng, D.,Regueiro-Ren, A.
Identification of benzothiazole derived monosaccharides as potent, selective, and orally bioavailable inhibitors of human and mouse galectin-3; a rare example of using a S···O binding interaction for drug design.
Bioorg.Med.Chem., 101:117638-117638, 2024

PubMed Abstract: As a result of our continued efforts to pursue Gal-3 inhibitors that could be used to fully evaluate the potential of Gal-3 as a therapeutic target, two novel series of benzothiazole derived monosaccharides as potent (against both human and mouse Gal-3) and orally bioavailable Gal-3 inhibitors, represented by 4 and 5, respectively, were identified. These discoveries were made based on proposals that the benzothiazole sulfur atom could interact with the carbonyl oxygen of G182/G196 in h/mGal-3, and that the anomeric triazole moiety could be modified into an N-methyl carboxamide functionality. The interaction between the benzothiazole sulfur and the carbonyl oxygen of G196 in mGal-3 was confirmed by an X-ray co-crystal structure of early lead 9, providing a rare example of using a S···O binding interaction for drug design. It was found that for both the series, methylation of 3-OH in the monosaccharides caused no loss in h & mGal-3 potencies but significantly improved permeability of the molecules.

PubMed: 38394996
DOI: 10.1016/j.bmc.2024.117638

Experimental method

X-RAY DIFFRACTION (1.8 Å)