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

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Bohari, Mohammad H
Yu, Xing
Kishor, Chandan
Patel, Brijesh
Go, Rob Marc
Seyedi, Hadieh A Eslampanah
Vinik, Yaron
Grice, I Darren
Zick, Yehiel
Blanchard, Helen
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2018
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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.

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ChemMedChem
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13
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16
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Medicinal and biomolecular chemistry
Medicinal and biomolecular chemistry not elsewhere classified
Organic chemistry
Pharmacology and pharmaceutical sciences
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