8Z25
Crystal structure of mouse Galectin-3 in complex with small molecule inhibitor
This is a non-PDB format compatible entry.
Summary for 8Z25
| Entry DOI | 10.2210/pdb8z25/pdb |
| Descriptor | Galectin-3, MAGNESIUM ION, 5-[(2~{S},3~{R},4~{R},5~{R},6~{R})-4-[4-[4-bromanyl-2,3-bis(fluoranyl)phenyl]-1,2,3-triazol-1-yl]-6-(hydroxymethyl)-3,5-bis(oxidanyl)oxan-2-yl]-4-[5-chloranyl-2-(trifluoromethyl)phenyl]-2-methyl-1,2,4-triazole-3-thione, ... (4 entities in total) |
| Functional Keywords | fibrosis, galactose, sugar binding protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 20070.15 |
| Authors | |
| Primary citation | Yoon, D.S.,Liu, C.,Jalagam, P.R.,Feng, J.,Wang, W.,Swidorski, J.J.,Xu, L.,Hartz, R.A.,Nair, S.K.,Beno, B.R.,Panda, M.,Ghosh, K.,Kumar, A.,Sale, H.,Shah, D.,Mathur, A.,Ellsworth, B.A.,Cheng, D.,Regueiro-Ren, A. Atropisomerism Observed in Galactose-Based Monosaccharide Inhibitors of Galectin-3 Comprising 2-Methyl-4-phenyl-2,4-dihydro-3 H -1,2,4-triazole-3-thione. J.Med.Chem., 67:14184-14199, 2024 Cited by PubMed Abstract: Galectin-3 (Gal-3) is a carbohydrate binding protein that has been implicated in the development and progression of fibrotic diseases. Proof-of-principal animal models have demonstrated that inhibition of Gal-3 is a potentially viable pathway for the treatment of fibrosis─with small molecule Gal-3 inhibitors advanced into clinical trials. We hereby report the discovery of novel galactose-based monosaccharide Gal-3 inhibitors comprising 2-methyl-4-phenyl-2,4-dihydro-3-1,2,4-triazole-3-thione (compound ) and 4-phenyl-4-1,2,4-triazole (compound ). Notably, hindered rotation caused by steric interaction between the 3-thione and -trifluoromethyl group of compounds , induced formation of thermodynamically stable atropisomers. Distinct X-ray cocrystal structures of and were obtained, which clearly demonstrated that the configuration of proscribes a key halogen bonding σ-hole interaction of 3-chloro with carbonyl oxygen of Gly182, thereby leading to significant loss in potency. Ultimately, and were evaluated in mouse pharmacokinetic studies, and both compounds exhibited oral exposures suitable for further assessment. PubMed: 39102502DOI: 10.1021/acs.jmedchem.4c01008 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.72 Å) |
Structure validation
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