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

Eur J Med Chem. 2021 Nov 5:223:113664. doi: 10.1016/j.ejmech.2021.113664. Epub 2021 Jun 25.

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 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.

Keywords: Benzimidazole; Galectin-8N; Molecular dynamics; Quinoline; Selectivity; X-ray crystallography.

MeSH terms

  • Benzimidazoles / chemistry*
  • Benzimidazoles / metabolism
  • Binding Sites
  • Crystallography, X-Ray
  • Drug Design*
  • Galactosides / chemistry*
  • Galactosides / metabolism
  • Galectins / chemistry*
  • Galectins / genetics
  • Galectins / metabolism
  • Humans
  • Kinetics
  • Ligands
  • Molecular Dynamics Simulation
  • Protein Binding
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / isolation & purification
  • Structure-Activity Relationship
  • Thermodynamics

Substances

  • Benzimidazoles
  • Galactosides
  • Galectins
  • LGALS8 protein, human
  • Ligands
  • Recombinant Proteins