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001-es BibID:	BIBFORM080579
035-os BibID:	(WoS)000476957100010 (Scopus)85068205459 (PMID)31243960
Első szerző:	Barr, Daniel
Cím:	Identification of C-[béta]-d-Glucopyranosyl Azole-Type Inhibitors of Glycogen Phosphorylase That Reduce Glycogenolysis in Hepatocytes : in Silico Design, Synthesis, in Vitro Kinetics, and ex Vivo Studies / Daniel Barr, Eszter Szennyes, Éva Bokor, Ziad H. Al-Oanzi, Colin Moffatt, Sándor Kun, Tibor Docsa, Ádám Sipos, Matthew P. Davies, Rachel T. Mathomes, Timothy J. Snape, Loranne Agius, László Somsák, Joseph M. Hayes
Dátum:	2019
ISSN:	1554-8929
Megjegyzések:	Several C-β-d-glucopyranosyl azoles have recently been uncovered as among the most potent glycogen phosphorylase (GP) catalytic site inhibitors discovered to date. Toward further exploring their translational potential, ex vivo experiments have been performed for their effectiveness in reduction of glycogenolysis in hepatocytes. New compounds for these experiments were predicted in silico where, for the first time, effective ranking of GP catalytic site inhibitor potencies using the molecular mechanics-generalized Born surface area (MM-GBSA) method has been demonstrated. For a congeneric training set of 27 ligands, excellent statistics in terms of Pearson (RP) and Spearman (RS) correlations (both 0.98), predictive index (PI = 0.99), and area under the receiver operating characteristic curve (AU-ROC = 0.99) for predicted versus experimental binding affinities were obtained, with ligand tautomeric/ionization states additionally considered using density functional theory (DFT). Seven 2-aryl-4(5)-(β-d-glucopyranosyl)-imidazoles and 2-aryl-4-(β-d-glucopyranosyl)-thiazoles were subsequently synthesized, and kinetics experiments against rabbit muscle GPb revealed new potent inhibitors with best Ki values in the low micromolar range (5c = 1.97 ?M; 13b = 4.58 ?M). Ten C-β-d-glucopyranosyl azoles were then tested ex vivo in mouse primary hepatocytes. Four of these (5a-c and 9d) demonstrated significant reduction of glucagon stimulated glycogenolysis (IC50 = 30-60 ?M). Structural and predicted physicochemical properties associated with their effectiveness were analyzed with permeability related parameters identified as crucial factors. The most effective ligand series 5 contained an imidazole ring, and the calculated pKa (Epik: 6.2; Jaguar 5.5) for protonated imidazole suggests that cellular permeation through the neutral state is favored, while within the cell, there is predicted more favorable binding to GP in the protonated form.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk
Megjelenés:	Acs Chemical Biology. - 14 : 7 (2019), p. 1460-1470. -
További szerzők:	Szennyes Eszter (1989-) (vegyész) Bokor Éva (1982-) (vegyész) Al-Oanzi, Ziad H. Moffatt, Colin Kun Sándor (1984-) (vegyész) Docsa Tibor (1975-) (vegyész, biokémikus) Sipos Ádám (1992-) (gyógyszerész) Davies, Matthew P. Mathomes, Rachel T. Snape, Timothy J. Agius, Loranne Somsák László (1954-) (vegyész) Hayes, Joseph M.
Pályázati támogatás:	GINOP-2.3.2-15-2016-00008 GINOP GINOP-2.3.3-15-2016-00004 GINOP
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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
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001-es BibID:	BIBFORM110220
035-os BibID:	(cikkazonosító)3005 (Scopus)85152313558 (WoS)000968814700001
Első szerző:	Kun Sándor (vegyész)
Cím:	Design and Synthesis of 3-(β-D-Glucopyranosyl)-4-amino/4-guanidino Pyrazole Derivatives and Analysis of Their Glycogen Phosphorylase Inhibitory Potential / Kun Sándor, Mathomes Rachel T., Docsa Tibor, Somsák László, Hayes Joseph M.
Dátum:	2023
ISSN:	1420-3049
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk
Megjelenés:	Molecules. - 28 : 7 (2023), p. 1-19. -
További szerzők:	Mathomes, Rachel T. Docsa Tibor (1975-) (vegyész, biokémikus) Somsák László (1954-) (vegyész) Hayes, Joseph M.
Pályázati támogatás:	FK132222 NKFIH
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