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001-es BibID:	BIBFORM003564
Első szerző:	Anagnostou, Eleni
Cím:	Crystallographic studies on two bioisosteric analogues, N-acetyl-beta-D-glucopyranosylamine and N-trifluoroacetyl-beta-D-glucopyranosylamine, potent inhibitors of muscle glycogen phosphorylase / Anagnostou E., Kosmopoulou N., Chrysina E.D., Leonidas D.D., Hadjiloi T., Tiraidis C., Zographos S.E., Györgydeák Z., Somsák L., Docsa T., Gergely P., Kolisis F.N., Oikonomakos N.G.
Dátum:	2006
Megjegyzések:	Structure-based inhibitor design has led to the discovery of a number of potent inhibitors of glycogen phosphorylase b (GPb), N-acyl derivatives of beta-D-glucopyranosylamine, that bind at the catalytic site of the enzyme. The first good inhibitor in this class of compounds, N-acetyl-beta-D-glucopyranosylamine (NAG) (Ki = 32 nM), has been previously characterized by biochemical, biological and crystallographic experiments at 2.3 A resolution. Bioisosteric replacement of the acetyl group by trifluoroacetyl group resulted in an inhibitor, N-trifluoroacetyl-beta-D-glucopyranosylamine (NFAG), with a Ki = 75 nM. To elucidate the structural basis of its reduced potency, we determined the ligand structure in complex with GPb at 1.8 A resolution. To compare the binding mode of N-trifluoroacetyl derivative with that of the lead molecule, we also determined the structure of GPb?NAG complex at a higher resolution (1.9 A). NFAG can be accommodated in the catalytic site of T-state GPb at approximately the same position as that of NAG and stabilize the T-state conformation of the 280s loop by making several favourable contacts to Asn284 of this loop. The difference observed in the Ki values of the two analogues can be interpreted in terms of subtle conformational changes of protein residues and shifts of water molecules in the vicinity of the catalytic site, variations in van der Waals interaction, and desolvation effects.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban type 2 diabetes glycogen phosphorylase N-acetyl-beta-D-glucopyranosylamine N-trifluoroacetyl-beta-D-glucopyranosylamine bioisosteric inhibition X-ray crystallography
Megjelenés:	Bioorganic and Meidicnal Chemistry 14 : 1 (2006), p. 181-189. -
További szerzők:	Kosmopoulou, Magda N. Chrysina, Evangelia D. Leonidas, Demetres D. Hadjiloi, Theodoros Tiraidis, Costantinos Zographos, Spyros E. Györgydeák Zoltán (1942-2005) (vegyész) Somsák László (1954-) (vegyész) Docsa Tibor (1975-) (vegyész, biokémikus) Gergely Pál (1947-) (biokémikus) Kolisis, Fragiskos N. Oikonomakos, George N.
Internet cím:	Intézményi repozitóriumban (DEA) tárolt változat DOI
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001-es BibID:	BIBFORM008742
Első szerző:	Chrysina, Evangelia D.
Cím:	Amide-1,2,3-triazole bioisosterism: the glycogen phosphorylase case / Evangelia D. Chrysina, Éva Bokor, Kyra-Melinda Alexacou, Maria-Despoina Charavgi, George N. Oikonomakos, Spyros E. Zographos, Demetres D. Leonidas, Nikos G. Oikonomakos, László Somsák
Dátum:	2009
Megjegyzések:	Per-O-acetylated beta-D-glucopyranosyl azide was transformed into an intermediate iminophosphorane by PMe3 which was then acylated to N-acyl-beta-D-glucopyranosylamines. The same azide and substituted acetylenes gave 1-(beta-D-glucopyranosyl)-4-substituted-1,2,3-triazoles in Cu(I)-catalyzed azide-alkyne cycloadditions. Deprotection of these products by the Zemplén method furnished beta-D-Glcp-NHCO-R derivatives as well as 1-(beta-D-Glcp)-4-R-1,2,3-triazoles which were evaluated as inhibitors of rabbit muscle glycogen phosphorylase b. Pairs of amides versus triazoles with the same R group displayed similar inhibition constants. X-ray crystallographic studies on the enzyme-inhibitor complexes revealed high similarities in the binding of pairs with R = 2-naphthyl and hydroxymethyl, while for the R = Ph and 1-naphthyl compounds a different orientation of the aromatic part and changes in the conformation of the 280s loop were observed. By this study new examples of amide-1,2,3-triazole bioisosteric relationship have been provided.
Tárgyszavak:	Természettudományok Kémiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:	Tetrahedron: Asymmetry. - 20 : 6-8 (2009), p. 733-740. -
További szerzők:	Bokor Éva (1982-) (vegyész) Alexacou, Kyra-Melinda Charavgi, Maria-Despoina Oikonomakos, George N. Zographos, Spyros E. Leonidas, Demetres D. Oikonomakos, Nikos G. Somsák László (1954-) (vegyész)
Internet cím:	DOI elektronikus változat
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001-es BibID:	BIBFORM004154
Első szerző:	Oikonomakos, George N.
Cím:	Advances in glycogen phosphorylase inhibitor design / Nikos G. Oikonomakos, László Somsák
Dátum:	2008
Megjegyzések:	The regulation of glycogen metabolism is a major therapeutic strategy for blood glucose control in type 2 diabetes. Because glycogen phosphorylase catalyzes the first step in the phosphorolysis of glycogen, it has become a potential key target for controlling hyperglycemia in this disease. This review focuses on advances in new, mostly synthetic, molecules that inhibit glycogen phosphorylase, and describes progress in our understanding of the mechanism of action of these inhibitors gained through X-ray crystallographic studies.
Tárgyszavak:	Természettudományok Kémiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban antihyperglycemics drug design enzyme binding site glycogen phosphorylase inhibitor hyperglycemia SAR type 2 diabetes X-ray crystallography
Megjelenés:	Current Opinion in Investigational Drugs. - 9 : 4 (2008), p. 379-395. -
További szerzők:	Somsák László (1954-) (vegyész)
Internet cím:	elektronikus változat
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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
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