Benzimidazole-galactosides bind selectively to the galectin-8 N-terminal domain : structure-based design and optimisation

Hassan, Mujtaba (author), van Klaveren, Sjors (author), Håkansson, Maria (author), Diehl, Carl (author), Kovačič, Rebeka (author), Baussière, Floriane (author), Sundin, Anders (author), Dernovšek, Jaka (author), Anderluh, Marko (author), Tomašič, Tihomir (author), Jakopin, Žiga (author)

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 1.6Å. 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%[micro]M 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.

• Language: English
• Keywords: benzimidazole, galectin-8N, quinoline, selectivity, molecular dynamics, x-ray crystallography
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2021
• Number of pages: Str. 1-13
• Numbering: art. 113664, Vol. 223
• PID: 20.500.12556/RUL-141507
• UDC: 615.4:54
• ISSN on article: 0223-5234
• DOI: 10.1016/j.ejmech.2021.113664
• COBISS.SI-ID: 68254211
• Publication date in RUL: 30.09.2022

Record is a part of a journal

• Title: European journal of medicinal chemistry
• Shortened title: Eur. j. med. chem.
• Publisher: Elsevier
• ISSN: 0223-5234
• COBISS.SI-ID: 25429760

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Projects

• Funder: Other - Other funder or multiple funders
• Funding programme: European Union’s Horizon 2020
• Project number: 765581