Investigation of the molecular details of the interactions of selenoglycosides and human galectin-3
| Autor: | Raics, Mária, Kálmán Balogh, Álex, Kishor, Chandan, Timári, István, Medrano, Francisco Javier, Romero, Antonio, Go, Rob Marc, Blanchard, Helen, Szilágyi, László, Kövér, Katalin E., Fehér, K. |
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| Přispěvatelé: | National Research, Development and Innovation Office (Hungary), European Commission, Hungarian Academy of Sciences, Ministry of Innovation and Technology (Hungary), Debrecen University, Kálmán Balogh, Álex, Kishor, Chandan, Timári, István, Medrano, Francisco Javier, Romero, Antonio, Go, Rob Marc, Blanchard, Helen, Szilágyi, László, Kövér, Katalin E. |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: | |
| Popis: | 17 p.-5 fig.-2 tab. 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. Our studies were supported by the National Research, Development and Innovation Office of Hungary (grant numbers: NN 128368 (to L.S.Z. and K.E.K.) and PD 135034 (to I.T.) and co-financed by the European Regional Development Fund (projects GINOP-2.3.3-15-2016-00004 and GINOP-2.3.2-15-2016-00008). The research of I.T. was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences (BO/00372/20/7) and the ÚNKP-21-5-DE-471 New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund. K.F. acknowledges the support of the János Bolyai Research Scholarship of the Hungarian Academy of Sciences (BO/004333/18/7) and the New National Excellence Program of Debrecen University (ÚNKP-21-4-DE-165 Bolyai+). We acknowledge the Governmental Information Technology Development Agency for awarding us access to supercomputing resources based in Debrecen, Hungary. |
| Databáze: | OpenAIRE |
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