Ligand Sulfur Oxidation State Progressively Alters Galectin-3-Ligand Complex Conformations To Induce
Mukul Mahanti1, Kumar Bhaskar Pal1, Rohit Kumar2
1Department of Chemistry, Lund University, Box 124, SE-221 00 Lund, Sweden.
Journal of Medicinal Chemistry
|October 25, 2023
Summary
Researchers modified galectin-3 ligands by altering sulfur oxidation states. The sulfone derivative significantly enhanced binding affinity through multiple hydrogen bonds, impacting immune regulation and tumor progression research.
Area of Science:
- Biochemistry
- Molecular Biology
- Medicinal Chemistry
Background:
- Galectins, particularly galectin-3, are crucial in immune regulation and tumor progression.
- High-affinity ligands for galectin-3 typically involve galactose cores and aryltriazole moieties, utilizing hydrophobic and π-stacking interactions.
Purpose of the Study:
- To design and synthesize novel thiogalactoside derivatives with varying sulfur oxidation states (sulfide, sulfoxide, sulfone).
- To investigate how these structural modifications influence ligand binding affinity and interaction modes with galectin-3.
- To explore the impact of hydrogen bonding, hydrophobic, and π-interactions on ligand-protein complex structure and thermodynamics.
Main Methods:
- Chemical synthesis of phenyl sulfone, sulfoxide, and sulfide-triazolyl thiogalactoside derivatives.
- X-ray crystallography to determine the structures of ligand-protein complexes.
- Thermodynamic analyses (e.g., isothermal titration calorimetry) to quantify binding affinities and energetics.
Main Results:
- Sulfoxide and sulfone ligands formed hydrogen bonds while maintaining π-interactions, leading to altered binding poses and improved affinities.
- The sulfoxide derivative showed decreased affinity compared to the sulfide.
- The sulfone derivative, forming three hydrogen bonds (two direct, one water-mediated), significantly increased binding affinity and altered the complex structure.
Conclusions:
- The oxidation state of sulfur in triazolyl thiogalactoside derivatives critically modulates interactions with galectin-3.
- Enhanced hydrogen bonding, particularly in the sulfone derivative, is key to increasing binding affinity and altering complex formation.
- These findings provide insights into designing potent galectin-3 inhibitors for therapeutic applications in immune and cancer biology.
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