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

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

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.

• Jezik: Angleški jezik
• Ključne besede: benzimidazole, galectin-8N, quinoline, selectivity, molecular dynamics, x-ray crystallography
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2021
• Št. strani: Str. 1-13
• Številčenje: art. 113664, Vol. 223
• PID: 20.500.12556/RUL-141507
• UDK: 615.4:54
• ISSN pri članku: 0223-5234
• DOI: 10.1016/j.ejmech.2021.113664
• COBISS.SI-ID: 68254211
• Datum objave v RUL: 30.09.2022

Gradivo je del revije

• Naslov: European journal of medicinal chemistry
• Skrajšan naslov: Eur. j. med. chem.
• Založnik: Elsevier
• ISSN: 0223-5234
• COBISS.SI-ID: 25429760

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Projekti

• Financer: Drugi - Drug financer ali več financerjev
• Program financ.: European Union’s Horizon 2020
• Številka projekta: 765581