Structure‐Based Design of a Monosaccharide Ligand Targeting Galectin‐8

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.