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

Mukul Mahanti, Kumar Bhaskar Pal, Rohit Kumar, Markus Schulze, Hakon Leffler, Derek T Logan, Ulf J Nilsson

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)14716–14723
Number of pages8
JournalJournal of Medicinal Chemistry
Volume66
Issue number21
DOIs
Publication statusPublished - 2023 Oct 25

Subject classification (UKÄ)

  • Organic Chemistry

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