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

DOI: 10.1016/j.ejmech.2021.113664 DOI Help

Authors: Mujtaba Hassan (Lund University; University of Ljubljana) , Sjors Van Klaveren (Lund University; University of Ljubljana) , Maria Håkansson (SARomics Biostructures AB) , Carl Diehl (SARomics Biostructures AB) , Rebeka Kovačič (SARomics Biostructures AB) , Floriane Baussière (Lund University) , Anders Sundin (Lund University) , Jaka Dernovšek (University of Ljubljana) , Björn Walse (SARomics Biostructures AB) , Fredrik Zetterberg (Galecto Biotech AB) , Hakon Leffler (Lund University) , Marko Anderluh (University of Ljubljana) , Tihomir Tomašič (University of Ljubljana) , Žiga Jakopin (University of Ljubljana) , Ulf J. Nilsson (Lund University)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: European Journal Of Medicinal Chemistry , VOL 19

State: Published (Approved)
Published: June 2021
Diamond Proposal Number(s): 23282

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.

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

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-Macromolecular Crystallography

Added On: 30/06/2021 10:46

Discipline Tags:

Organic Chemistry Life Sciences & Biotech Health & Wellbeing Drug Discovery Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)