Department of Chemistry, Lund University, Box 124, SE-221 00 Lund, Sweden.
Division of Biochemistry & Structural Biology, Centre for Molecular Protein Science, Department of Chemistry, Lund University, Box 124, SE-221 00 Lund, Sweden.
J Med Chem. 2023 Nov 9;66(21):14716-14723. doi: 10.1021/acs.jmedchem.3c01223. Epub 2023 Oct 25.
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.
半乳糖凝集素在免疫调节和肿瘤进展中发挥着重要的生物学作用。与浅层亲水性半乳糖凝集素-3 配体结合位点具有高亲和力的配体主要依赖于带有附加芳基三唑部分的半乳糖核心，形成疏水相互作用和π堆积。我们设计并合成了苯砜、亚砜和硫代三唑基硫代半乳糖苷衍生物，以创造增强亲和力的氢键、疏水和π相互作用。晶体结构和热力学分析表明，亚砜和砜配体形成氢键的同时保留了π相互作用，从而提高了亲和力并形成独特的结合构象。与硫代物相比，带有一个氢键受体的亚砜导致亲和力降低，而相应的砜则形成三个氢键，其中两个分别与 Asn 和 Arg 侧链直接形成，一个通过水分子与 Asp 侧链形成，这分别改变了复合物的结构并增加了亲和力。这些发现强调了硫氧化态对半乳糖凝集素与配体相互作用的热力学和结构都有影响。
