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Strong Binding of C-Glycosylic1,2-Thiodisaccharides to Galectin-3─Enthalpy-Driven Affinity Enhancement by Water-Mediated Hydrogen Bonds

Lázár, László ; Tsagkarakou, Anastasia S ; Stravodimos, George ; Kontopidis, George ; Leffler, Hakon LU ; Nilsson, Ulf J LU ; Somsák, László and Leonidas, Demetres D (2023) In Journal of Medicinal Chemistry 66(17). p.12420-12431
Abstract

Galectin-3 is involved in multiple pathways of many diseases, including cancer, fibrosis, and diabetes, and it is a validated pharmaceutical target for the development of novel therapeutic agents to address unmet medical needs. Novel 1,2-thiodisaccharides with a C-glycosylic functionality were synthesized by the photoinitiated thiol-ene click reaction of O-peracylated 1-C-substituted glycals and 1-thio-glycopyranoses. Subsequent global deprotection yielded test compounds, which were studied for their binding to human galectin-3 by fluorescence polarization and isothermal titration calorimetry to show low micromolar K d values. The best inhibitor displayed a K d value of 8.0 μM. An analysis of the thermodynamic binding parameters... (More)

Galectin-3 is involved in multiple pathways of many diseases, including cancer, fibrosis, and diabetes, and it is a validated pharmaceutical target for the development of novel therapeutic agents to address unmet medical needs. Novel 1,2-thiodisaccharides with a C-glycosylic functionality were synthesized by the photoinitiated thiol-ene click reaction of O-peracylated 1-C-substituted glycals and 1-thio-glycopyranoses. Subsequent global deprotection yielded test compounds, which were studied for their binding to human galectin-3 by fluorescence polarization and isothermal titration calorimetry to show low micromolar K d values. The best inhibitor displayed a K d value of 8.0 μM. An analysis of the thermodynamic binding parameters revealed that the binding Gibbs free energy (Δ G) of the new inhibitors was dominated by enthalpy (Δ H). The binding mode of the four most efficient 1,2-thiodisaccharides was also studied by X-ray crystallography that uncovered the unique role of water-mediated hydrogen bonds in conferring enthalpy-driven affinity enhancement for the new inhibitors. This 1,2-thiodisaccharide-type scaffold represents a new lead for galectin-3 inhibitor discovery and offers several possibilities for further development.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Humans, Galectin 3, Hydrogen Bonding, Galectins, Thermodynamics, Water
in
Journal of Medicinal Chemistry
volume
66
issue
17
pages
12 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • scopus:85171309454
  • pmid:37658813
ISSN
1520-4804
DOI
10.1021/acs.jmedchem.3c00882
language
English
LU publication?
yes
id
67a2f9c2-d1bd-4dc3-a846-cc80a973dad6
date added to LUP
2023-09-28 08:45:53
date last changed
2024-04-19 01:45:44
@article{67a2f9c2-d1bd-4dc3-a846-cc80a973dad6,
  abstract     = {{<p>Galectin-3 is involved in multiple pathways of many diseases, including cancer, fibrosis, and diabetes, and it is a validated pharmaceutical target for the development of novel therapeutic agents to address unmet medical needs. Novel 1,2-thiodisaccharides with a  C-glycosylic functionality were synthesized by the photoinitiated thiol-ene click reaction of  O-peracylated 1-C-substituted glycals and 1-thio-glycopyranoses. Subsequent global deprotection yielded test compounds, which were studied for their binding to human galectin-3 by fluorescence polarization and isothermal titration calorimetry to show low micromolar K d values. The best inhibitor displayed a  K d value of 8.0 μM. An analysis of the thermodynamic binding parameters revealed that the binding Gibbs free energy (Δ  G) of the new inhibitors was dominated by enthalpy (Δ H). The binding mode of the four most efficient 1,2-thiodisaccharides was also studied by X-ray crystallography that uncovered the unique role of water-mediated hydrogen bonds in conferring enthalpy-driven affinity enhancement for the new inhibitors. This 1,2-thiodisaccharide-type scaffold represents a new lead for galectin-3 inhibitor discovery and offers several possibilities for further development. </p>}},
  author       = {{Lázár, László and Tsagkarakou, Anastasia S and Stravodimos, George and Kontopidis, George and Leffler, Hakon and Nilsson, Ulf J and Somsák, László and Leonidas, Demetres D}},
  issn         = {{1520-4804}},
  keywords     = {{Humans; Galectin 3; Hydrogen Bonding; Galectins; Thermodynamics; Water}},
  language     = {{eng}},
  month        = {{09}},
  number       = {{17}},
  pages        = {{12420--12431}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{Journal of Medicinal Chemistry}},
  title        = {{Strong Binding of        C-Glycosylic1,2-Thiodisaccharides to Galectin-3─Enthalpy-Driven Affinity Enhancement by Water-Mediated Hydrogen Bonds}},
  url          = {{http://dx.doi.org/10.1021/acs.jmedchem.3c00882}},
  doi          = {{10.1021/acs.jmedchem.3c00882}},
  volume       = {{66}},
  year         = {{2023}},
}