Abstract
Human galectin-3 (hGal-3) is involved in a variety of biological processes and is implicated in wide range of diseases. As a result, targeting hGal-3 for clinical applications has become an intense area of research. As a step towards the development of novel hGal-3 inhibitors, we describe a study of the binding of two Se-containing hGal-3 inhibitors, specifically that of di(β-D-galactopyranosyl)selenide (SeDG), in which two galactose rings are linked by one Se atom and a di(β-D-galactopyranosyl)diselenide (DSeDG) analogue with a diseleno bond between the two sugar units. The binding affinities of these derivatives to hGal-3 were determined by 15N-1H HSQC NMR spectroscopy and fluorescence anisotropy titrations in solution, indicating a slight decrease in the strength of interaction for SeDG compared to thiodigalactoside (TDG), a well-known inhibitor of hGal-3, while DSeDG displayed a much weaker interaction strength. NMR and FA measurements showed that both seleno derivatives bind to the canonical S face site of hGal-3 and stack against the conserved W181 residue also confirmed by X-ray crystallography, revealing canonical properties of the interaction. The interaction with DSeDG revealed two distinct binding modes in the crystal structure which are in fast exchange on the NMR time scale in solution, explaining a weaker interaction with hGal-3 than SeDG. Using molecular dynamics simulations, we have found that energetic contributions to the binding enthalpies mainly differ in the electrostatic interactions and in polar solvation terms and are responsible for weaker binding of DSeDG compared to SeDG. Selenium-containing carbohydrate inhibitors of hGal-3 showing canonical binding modes offer the potential of becoming novel hydrolytically stable scaffolds for a new class of hGal-3 inhibitors.
Highlights
Human galectin-3, one of the adhesion/growth-regulatory galactose-binding lectins, plays a key role in many different physiological and pathological processes, Int
This is best suited for monitoring weak interactions in the HSQC titration spectra
The atomic structures of the galectin-3 carbohydratefold recognition domain (CRD) specifically that of di(β-Dgalactopyranosyl)selenide (SeDG) and DSeDG complexes were solved by molecular replacement using a search model of the galectin-3 CRD (PDB ID: 2NMO [32]), and REFMAC5 was used for atomic model refinement [54]
Summary
Human galectin-3 (hGal-3), one of the adhesion/growth-regulatory galactose-binding lectins, plays a key role in many different physiological and pathological processes, . 2022, 23, 2494 it is involved in a wide variety of diseases such as cancer, inflammation and fibrosis, heart disease and Asofone of its main actions, hGal‐3 β‐. Sci. 2022, 23, 2494 it is involved in a wide variety of diseases such as cancer, inflammation and fibrosis, heart disease and Asofone of its main actions, hGal‐3 β‐ It is involved in astroke wide [1–4]. TDG displayed a comparable activity to the natural ligands of natural ligands of hGal‐3 [17] and was used extensively as a starting scaffold for further hGal-3 [17] and was used extensively as a starting scaffold for further derivatives [19–23]. Report, we investigate the details of the hGal-3 binding of two seleno derivatives, SeDG tives, SeDG and DSeDG (Scheme 1a,b, respectively).
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