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

Journal Article


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-8N). 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-8N. Isothermal titration calorimetry (ITC) determined that the binding affinity of galectin-8N for 6 was 32.8 μm, whereas no significant affinity was detected for the C-terminal domain of galectin-8 (galectin-8C). The crystal structure of the galectin-8N–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-8N 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.

Publication Date


  • 2018

Citation


  • Bohari, M. H., Yu, X., Kishor, C., Patel, B., Go, R. M., Eslampanah Seyedi, H. A., . . . Blanchard, H. (2018). Structure-Based Design of a Monosaccharide Ligand Targeting Galectin-8. ChemMedChem, 13(16), 1664-1672. doi:10.1002/cmdc.201800224

Scopus Eid


  • 2-s2.0-85050583874

Start Page


  • 1664

End Page


  • 1672

Volume


  • 13

Issue


  • 16

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-8N). 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-8N. Isothermal titration calorimetry (ITC) determined that the binding affinity of galectin-8N for 6 was 32.8 μm, whereas no significant affinity was detected for the C-terminal domain of galectin-8 (galectin-8C). The crystal structure of the galectin-8N–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-8N 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.

Publication Date


  • 2018

Citation


  • Bohari, M. H., Yu, X., Kishor, C., Patel, B., Go, R. M., Eslampanah Seyedi, H. A., . . . Blanchard, H. (2018). Structure-Based Design of a Monosaccharide Ligand Targeting Galectin-8. ChemMedChem, 13(16), 1664-1672. doi:10.1002/cmdc.201800224

Scopus Eid


  • 2-s2.0-85050583874

Start Page


  • 1664

End Page


  • 1672

Volume


  • 13

Issue


  • 16