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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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001-es BibID:	BIBFORM112085
035-os BibID:	(cikkazonosító)4359 (Scopus)85161668681 (WoS)001005434600001
Első szerző:	Kola, Job Baffin (PhD hallgató)
Cím:	Stretch-Induced Down-Regulation of HCN2 Suppresses Contractile Activity / Job Baffin Kola, Botagoz Turarova, Dora Csige, Ádám Sipos, Luca Varga, Bence Gergely, Farah Al Refai, Iván P. Uray, Tibor Docsa, Karen Uray
Dátum:	2023
ISSN:	1420-3049
Megjegyzések:	Although hyperpolarization-activated and cyclic nucleotide-gated 2 channels (HCN2) are expressed in multiple cell types in the gut, the role of HCN2 in intestinal motility is poorly understood. HCN2 is down-regulated in intestinal smooth muscle in a rodent model of ileus. Thus, the purpose of this study was to determine the effects of HCN inhibition on intestinal motility. HCN inhibition with ZD7288 or zatebradine significantly suppressed both spontaneous and agonist-induced contractile activity in the small intestine in a dose-dependent and tetrodotoxin-independent manner. HCN inhibition significantly suppressed intestinal tone but not contractile amplitude. The calcium sensitivity of contractile activity was significantly suppressed by HCN inhibition. Inflammatory mediators did not affect the suppression of intestinal contractile activity by HCN inhibition but increased stretch of the intestinal tissue partially attenuated the effects of HCN inhibition on agonist-induced intestinal contractile activity. HCN2 protein and mRNA levels in intestinal smooth muscle tissue were significantly down-regulated by increased mechanical stretch compared to unstretched tissue. Increased cyclical stretch down-regulated HCN2 protein and mRNA levels in primary human intestinal smooth muscle cells and macrophages. Overall, our results suggest that decreased HCN2 expression induced by mechanical signals, such as intestinal wall distension or edema development, may contribute to the development of ileus.
Tárgyszavak:	Természettudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk
Megjelenés:	Molecules. - 28 : 11 (2023), p. 1-14. -
További szerzők:	Turarova, Botagoz Csige Dóra (1996-) (molekuláris biológus) Sipos Ádám (1992-) (gyógyszerész) Varga Luca Gergely Bence (1995-) (molekuláris biológus) Refai, Farah Al Uray Iván Péter (1970-) (kutatóorvos) Docsa Tibor (1975-) (vegyész, biokémikus) Uray Karen (1964-) (biokémikus)
Pályázati támogatás:	EFOP-3.6.2-16-2017-00006 EFOP
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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