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Crystallographic studies on two bioisosteric analogues, N-acetyl-beta-D-glucopyranosylamine and N-trifluoroacetyl-beta-D-glucopyranosylamine, potent inhibitors of muscle glycogen phosphorylase

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dc.contributor.author Anagnostou, E en
dc.contributor.author Kosmopoulou, MN en
dc.contributor.author Chrysina, ED en
dc.contributor.author Leonidas, DD en
dc.contributor.author Hadjiloi, T en
dc.contributor.author Tiraidis, C en
dc.contributor.author Zographos, SE en
dc.contributor.author Gyorgydeak, Z en
dc.contributor.author Somsak, L en
dc.contributor.author Docsa, T en
dc.contributor.author Gergely, P en
dc.contributor.author Kolisis, FN en
dc.contributor.author Oikonomakos, NG en
dc.date.accessioned 2014-03-01T01:55:31Z
dc.date.available 2014-03-01T01:55:31Z
dc.date.issued 2006 en
dc.identifier.issn 0968-0896 en
dc.identifier.uri https://dspace.lib.ntua.gr/xmlui/handle/123456789/27775
dc.subject type 2 diabetes en
dc.subject glycogen phosphorylase en
dc.subject N-acetyl-beta-D-glucopyranosylamine en
dc.subject N-trifluoroacetyl-beta-D-glucopyranosylamine en
dc.subject bioisosteric inhibition en
dc.subject X-ray crystallography en
dc.subject.classification Biochemistry & Molecular Biology en
dc.subject.classification Chemistry, Medicinal en
dc.subject.classification Chemistry, Organic en
dc.subject.other GLUCOSE ANALOG en
dc.subject.other BINDING-AFFINITY en
dc.subject.other SPIROHYDANTOIN en
dc.subject.other HEPATOCYTES en
dc.subject.other RESOLUTION en
dc.subject.other MECHANISM en
dc.subject.other SYNTHASE en
dc.subject.other DESIGN en
dc.subject.other LIVER en
dc.subject.other STATE en
dc.title Crystallographic studies on two bioisosteric analogues, N-acetyl-beta-D-glucopyranosylamine and N-trifluoroacetyl-beta-D-glucopyranosylamine, potent inhibitors of muscle glycogen phosphorylase en
heal.type journalArticle en
heal.language English en
heal.publicationDate 2006 en
heal.abstract Structure-based inhibitor design hits 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) (K-i = 32 mu M), has been previously characterized by biochemical, biological and crystallographic experiments at 2.3 angstrom resolution. Bioisosteric replacement of the acetyl group by trifluoroacetyl group resulted in an inhibitor, N-trifluoroacetyl-beta-D-glucopyranosylamine (NFAG), with a K-i = 75 mu M. To elucidate the structural basis of its reduced potency, we determined the ligand Structure in complex with GPb at 1.8 angstrom 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 angstrom). 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. (c) 2005 Elsevier Ltd. All rights reserved. en
heal.publisher PERGAMON-ELSEVIER SCIENCE LTD en
heal.journalName BIOORGANIC & MEDICINAL CHEMISTRY en
dc.identifier.isi ISI:000233708900020 en
dc.identifier.volume 14 en
dc.identifier.issue 1 en
dc.identifier.spage 181 en
dc.identifier.epage 189 en


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