Ligand Sulfur Oxidation State Progressively Alters Galectin-3-Ligand Complex Conformations To Induce Affinity-Influencing Hydrogen Bonds

Galectins play biological roles in immune regulation
and tumor
progression. Ligands with high affinity for the shallow, hydrophilic
galectin-3 ligand binding site rely primarily on a galactose core
with appended aryltriazole moieties, making hydrophobic interactions
and π-stacking. We designed and synthesized phenyl sulfone,
sulfoxide, and sulfide-triazolyl thiogalactoside derivatives to create
affinity-enhancing hydrogen bonds, hydrophobic and π-interactions.
Crystal structures and thermodynamic analyses revealed that the sulfoxide
and sulfone ligands form hydrogen bonds while retaining π-interactions,
resulting in improved affinities and unique binding poses. The sulfoxide,
bearing one hydrogen bond acceptor, leads to an affinity decrease
compared to the sulfide, whereas the corresponding sulfone forms three
hydrogen bonds, two directly with Asn and Arg side chains and one
water-mediated to an Asp side chain, respectively, which alters the
complex structure and increases affinity. These findings highlight
that the sulfur oxidation state influences both the interaction thermodynamics
and structure.