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1.
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
Internet cím:
Szerző által megadott URL
DOI
Intézményi repozitóriumban (DEA) tárolt változat
Borító:
Saját polcon:
2.
001-es BibID:
BIBFORM072396
Első szerző:
Kun Sándor (vegyész)
Cím:
A multidisciplinary study of 3-(β-D-glucopyranosyl)-5-substituted-1,2,4-triazole derivatives as glycogen phosphorylase inhibitors : computation, synthesis, crystallography and kinetics reveal new potent inhibitors / Sandor Kun, Jaida Begum, Efthimios Kyriakis, Evgenia C. V. Stamati, Thomas A. Barkas, Eszter Szennyes, Eva Bokor, Katalin E. Szabo, George A. Stravodimos, Adam Sipos, Tibor Docsa, Pal Gergely, Colin Moffatt, Myrto S. Patraskaki, Maria C. Kokolaki, Alkistis Gkerdi, Vassiliki T. Skamnaki, Demetres D. Leonidas, Laszló Somsák, Joseph M. Hayes
Dátum:
2018
ISSN:
0223-5234
Megjegyzések:
3-(β-D-Glucopyranosyl)-5-substituted-1,2,4-triazoles have been revealed as an effective scaffold for the development of potent glycogen phosphorylase (GP) inhibitors but with the potency very sensitive to the nature of the alkyl/aryl 5-substituent (Kun et al., Eur. J. Med. Chem. 2014, 76, 567). For a training set of these ligands, quantum mechanics-polarized ligand docking (QM-PLD) demonstrated good potential to identify larger differences in potencies (predictive index PI = 0.82) and potent inhibitors with Ki's < 10 ?M (AU-ROC = 0.86). Accordingly, in silico screening of 2335 new analogues exploiting the ZINC docking database was performed and nine predicted candidates selected for synthesis. The compounds were prepared in O-perbenzoylated forms by either ring transformation of 5-?-D-glucopyranosyl tetrazole by N-benzyl-arenecarboximidoyl chlorides, ring closure of C-(?-D-glucopyranosyl)formamidrazone with aroyl chlorides, or that of N-(?-D-glucopyranosylcarbonyl)arenethiocarboxamides by hydrazine, followed by deprotections. Kinetics experiments against rabbit muscle GPb (rmGPb) and human liver GPa (hlGPa) revealed five compounds as potent low ?M inhibitors with three of these on the submicromolar range for rmGPa. X-ray crystallographic analysis sourced the potency to a combination of favorable interactions from the 1,2,4-triazole and suitable aryl substituents in the GP catalytic site. The compounds also revealed promising calculated pharmacokinetic profiles.
Tárgyszavak:
Orvostudományok
Elméleti orvostudományok
idegen nyelvű folyóiratközlemény külföldi lapban
1,2,4-Triazole
C-[beta]-D-glucopyranosyl derivatives
Glycogen phosphorylase inhibitors
QM/MM docking
Kinetics
X-ray crystallography
Megjelenés:
European Journal of Medicinal Chemistry 147 (2018), p. 266-278. -
További szerzők:
Begum, Jaida
Kyriakis, Efthimios
Stamati, Evgenia C. V.
Barkas, Thomas A.
Szennyes Eszter (1989-) (vegyész)
Bokor Éva (1982-) (vegyész)
Szabó Erzsébet Katalin (1989-) (vegyész)
Stravodimos, George A.
Sipos Ádám (1992-) (gyógyszerész)
Docsa Tibor (1975-) (vegyész, biokémikus)
Gergely Pál (1947-) (biokémikus)
Moffatt, Colin
Patraskaki, Myrto S.
Kokolaki, Maria C.
Gkerdi, Alkistis
Skamnaki, Vassiliki T.
Leonidas, Demetres D.
Somsák László (1954-) (vegyész)
Hayes, Joseph M.
Pályázati támogatás:
PD 105808
OTKA
PD 121406
OTKA
GINOP-2.3.2-15-2016-00008
GINOP
Internet cím:
Szerző által megadott URL
DOI
Intézményi repozitóriumban (DEA) tárolt változat
Borító:
Saját polcon:
3.
001-es BibID:
BIBFORM006384
Első szerző:
Somsák László (vegyész)
Cím:
New inhibitors of glycogen phosphorylase as potential antidiabetic agents / L. Somsák, K. Czifrák, M. Tóth, É. Bokor, E. D. Chrysina, K.-M. Alexacou, J. M. Hayes, C. Tiraidis, E. Lazoura, D. D. Leonidas, S. E. Zographos, N. G. Oikonomakos
Dátum:
2008
ISSN:
0929-8673
Megjegyzések:
The protein glycogen phosphorylase has been linked to type 2 diabetes, indicating the importance of this target to human health. Hence, the search for potent and selective inhibitors of this enzyme, which may lead to antihyperglycaemic drugs, has received particular attention. Glycogen phosphorylase is a typical allosteric protein with five different ligand binding sites, thus offering multiple opportunities for modulation of enzyme activity. The present survey is focused on recent new molecules, potential inhibitors of the enzyme. The biological activity can be modified by these molecules through direct binding, allosteric effects or other structural changes. Progress in our understanding of the mechanism of action of these inhibitors has been made by the determination of high-resolution enzyme inhibitor structures (both muscle and liver). The knowledge of the three-dimensional structures of protein-ligand complexes allows analysis of how the ligands interact with the target and has the potential to facilitate structure-based drug design. In this review, the synthesis, structure determination and computational studies of the most recent inhibitors of glycogen phosphorylase at the different binding sites are presented and analyzed.
Tárgyszavak:
Természettudományok
Kémiai tudományok
idegen nyelvű folyóiratközlemény külföldi lapban
glycogen phosphorylase
inhibitor
type 2 diabetes
structure-based drug design
antidiabetic agent
Megjelenés:
Current Medicinal Chemistry. - 15 : 28 (2008), p. 2933-2983. -
További szerzők:
Czifrák Katalin (1978-) (vegyész)
Tóth Marietta (1974-) (vegyész)
Bokor Éva (1982-) (vegyész)
Chrysina, Evangelia D.
Alexacou, Kyra-Melinda
Hayes, Joseph M.
Tiraidis, Costantinos
Lazoura, E.
Leonidas, Demetres D.
Zographos, Spyros E.
Oikonomakos, George N.
Internet cím:
elektronikus változat
Borító:
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