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Benzimidazole–galactosides bind selectively to the Galectin-8 N-Terminal domain : Structure-based design and optimisation

Hassan, Mujtaba LU ; van Klaveren, Sjors LU ; Håkansson, Maria LU ; Diehl, Carl LU ; Kovačič, Rebeka ; Baussière, Floriane ; Sundin, Anders P. LU ; Dernovšek, Jaka ; Walse, Björn LU and Zetterberg, Fredrik , et al. (2021) In European Journal of Medicinal Chemistry 223.
Abstract

We have obtained the X-ray crystal structure of the galectin-8 N-terminal domain (galectin-8N) with a previously reported quinoline–galactoside ligand at a resolution of 1.6 Å. Based on this X-ray structure, a collection of galactosides derivatised at O3 with triazole, benzimidazole, benzothiazole, and benzoxazole moieties were designed and synthesised. This led to the discovery of a 3-O-(N-methylbenzimidazolylmethyl)–galactoside with a Kd of 1.8 μM for galectin-8N, the most potent selective synthetic galectin-8N ligand to date. Molecular dynamics simulations showed that benzimidazole–galactoside derivatives bind the non-conserved amino acid Gln47, accounting for the higher selectivity for galectin-8N. Galectin-8 is a... (More)

We have obtained the X-ray crystal structure of the galectin-8 N-terminal domain (galectin-8N) with a previously reported quinoline–galactoside ligand at a resolution of 1.6 Å. Based on this X-ray structure, a collection of galactosides derivatised at O3 with triazole, benzimidazole, benzothiazole, and benzoxazole moieties were designed and synthesised. This led to the discovery of a 3-O-(N-methylbenzimidazolylmethyl)–galactoside with a Kd of 1.8 μM for galectin-8N, the most potent selective synthetic galectin-8N ligand to date. Molecular dynamics simulations showed that benzimidazole–galactoside derivatives bind the non-conserved amino acid Gln47, accounting for the higher selectivity for galectin-8N. Galectin-8 is a carbohydrate-binding protein that plays a key role in pathological lymphangiogenesis, modulation of the immune system, and autophagy. Thus, the benzimidazole-derivatised galactosides represent promising compounds for studies of the pathological implications of galectin-8, as well as a starting point for the development of anti-tumour and anti-inflammatory therapeutics targeting galectin-8.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
Benzimidazole, Galectin-8N, Molecular dynamics, Quinoline, Selectivity, X-ray crystallography
in
European Journal of Medicinal Chemistry
volume
223
article number
113664
publisher
Elsevier Masson SAS
external identifiers
  • pmid:34225180
  • scopus:85108944997
ISSN
0223-5234
DOI
10.1016/j.ejmech.2021.113664
language
English
LU publication?
yes
id
fa919e77-cb59-4772-b755-3e3534a0ebd9
date added to LUP
2021-08-13 15:12:27
date last changed
2024-06-29 15:20:14
@article{fa919e77-cb59-4772-b755-3e3534a0ebd9,
  abstract     = {{<p>We have obtained the X-ray crystal structure of the galectin-8 N-terminal domain (galectin-8N) with a previously reported quinoline–galactoside ligand at a resolution of 1.6 Å. Based on this X-ray structure, a collection of galactosides derivatised at O3 with triazole, benzimidazole, benzothiazole, and benzoxazole moieties were designed and synthesised. This led to the discovery of a 3-O-(N-methylbenzimidazolylmethyl)–galactoside with a K<sub>d</sub> of 1.8 μM for galectin-8N, the most potent selective synthetic galectin-8N ligand to date. Molecular dynamics simulations showed that benzimidazole–galactoside derivatives bind the non-conserved amino acid Gln47, accounting for the higher selectivity for galectin-8N. Galectin-8 is a carbohydrate-binding protein that plays a key role in pathological lymphangiogenesis, modulation of the immune system, and autophagy. Thus, the benzimidazole-derivatised galactosides represent promising compounds for studies of the pathological implications of galectin-8, as well as a starting point for the development of anti-tumour and anti-inflammatory therapeutics targeting galectin-8.</p>}},
  author       = {{Hassan, Mujtaba and van Klaveren, Sjors and Håkansson, Maria and Diehl, Carl and Kovačič, Rebeka and Baussière, Floriane and Sundin, Anders P. and Dernovšek, Jaka and Walse, Björn and Zetterberg, Fredrik and Leffler, Hakon and Anderluh, Marko and Tomašič, Tihomir and Jakopin, Žiga and Nilsson, Ulf J.}},
  issn         = {{0223-5234}},
  keywords     = {{Benzimidazole; Galectin-8N; Molecular dynamics; Quinoline; Selectivity; X-ray crystallography}},
  language     = {{eng}},
  month        = {{11}},
  publisher    = {{Elsevier Masson SAS}},
  series       = {{European Journal of Medicinal Chemistry}},
  title        = {{Benzimidazole–galactosides bind selectively to the Galectin-8 N-Terminal domain : Structure-based design and optimisation}},
  url          = {{http://dx.doi.org/10.1016/j.ejmech.2021.113664}},
  doi          = {{10.1016/j.ejmech.2021.113664}},
  volume       = {{223}},
  year         = {{2021}},
}