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Structure‐Based Design of a Monosaccharide Ligand Targeting Galectin‐8
Author(s) -
Bohari Mohammad H.,
Yu Xing,
Kishor Chandan,
Patel Brijesh,
Go Rob Marc,
Eslampanah Seyedi Hadieh A.,
Vinik Yaron,
Grice I. Darren,
Zick Yehiel,
Blanchard Helen
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800224
Subject(s) - isothermal titration calorimetry , galectin , chemistry , ligand (biochemistry) , galectin 1 , galectin 3 , rational design , galactose , stereochemistry , biochemistry , biology , nanotechnology , microbiology and biotechnology , receptor , materials science , immunology
Abstract Galectin‐8 is a β‐galactoside‐recognising protein that has a role in the regulation of bone remodelling and is an emerging new target for tackling diseases with associated bone loss. We have designed and synthesised methyl 3‐ O ‐[1‐carboxyethyl]‐β‐ d ‐galactopyranoside (compound 6 ) as a ligand to target the N‐terminal domain of galectin‐8 (galectin‐8 N ). Our design involved molecular dynamics (MD) simulations that predicted 6 to mimic the interactions made by the galactose ring as well as the carboxylic acid group of 3′‐ O ‐sialylated lactose (3′‐SiaLac), with galectin‐8 N . Isothermal titration calorimetry (ITC) determined that the binding affinity of galectin‐8 N for 6 was 32.8 μ m , whereas no significant affinity was detected for the C‐terminal domain of galectin‐8 (galectin‐8 C ). The crystal structure of the galectin‐8 N – 6 complex validated the predicted binding conformation and revealed the exact protein–ligand interactions that involve evolutionarily conserved amino acids of galectin and also those unique to galectin‐8 N for recognition. Overall, we have initiated and demonstrated a rational ligand design campaign to develop a monosaccharide‐based scaffold as a binder of galectin‐8.