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001-es BibID:	BIBFORM120792
Első szerző:	Homolya Levente (vegyész)
Cím:	Synthesis, in silico and kinetics evaluation of N-(beta-D-glucopyranosyl)-2-arylimidazole-4(5)-carboxamides and N-(beta-D-glucopyranosyl)-4(5)-arylimidazole-2-carboxamides as glycogen phosphorylase inhibitors / Levente Homolya, Rachel T. Mathomes, Luca Varga, Tibor Docsa, László Juhász, Joseph M. Hayes, László Somsák
Dátum:	2024
ISSN:	1422-0067
Megjegyzések:	Recently studied N-(?-D-glucopyranosyl)-3-aryl-1,2,4-triazole-5-carboxamides have proven to be low micromolar inhibitors of glycogen phosphorylase (GP), a validated target for the treatment of type 2 diabetes mellitus. Since in other settings, the bioisosteric replacement of the 1,2,4-triazole moiety with imidazole resulted in significantly more efficient GP inhibitors, in silico calculations using Glide molecular docking along with unbound state DFT calculations were performed on N-(?-Dglucopyranosyl)-arylimidazole-carboxamides, revealing their potential for strong GP inhibition. The syntheses of the target compounds involved the formation of an amide bond between per-O-acetylated ?-D-glucopyranosylamine and the corresponding arylimidazole-carboxylic acids. Kinetics experiments on rabbit muscle GPb revealed low micromolar inhibitors, with the best inhibition constants (Kis) of ~3?4 ?M obtained for 1- and 2-naphthyl-substituted N-(?-D-glucopyranosyl)-imidazolecarboxamides, 2b?c. The predicted protein?ligand interactions responsible for the observed potencies are discussed and will facilitate the structure-based design of other inhibitors targeting this important therapeutic target. Meanwhile, the importance of the careful consideration of ligand tautomeric states in binding calculations is highlighted, with the usefulness of DFT calculations in this regard proposed.
Tárgyszavak:	Természettudományok Kémiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk glucose analogues glycogen phosphorylase inhibitor tautomers type 2 diabetes
Megjelenés:	International Journal Of Molecular Sciences. - 25 : 9 (2024), p. 1-21. -
További szerzők:	Mathomes, Rachel T. Varga Luca Docsa Tibor (1975-) (vegyész, biokémikus) Juhász László (1973-) (vegyész) Hayes, Joseph M. Somsák László (1954-) (vegyész)
Pályázati támogatás:	K146147 OTKA GINOP-2.3.2-15-2016-00008 GINOP GINOP-2.3.3-15-2016-00004 GINOP
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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