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

Anagnostou, E; Kosmopoulou, MN; Chrysina, ED; Leonidas, DD; Hadjiloi, T; Tiraidis, C; Zographos, SE; Gyorgydeak, Z; Somsak, L; Docsa, T; Gergely, P; Kolisis, FN; Oikonomakos, NG

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	2014-03-01T01:23:45Z
dc.date.available	2014-03-01T01:23:45Z
dc.date.issued	2006	en
dc.identifier.issn	09680896	en
dc.identifier.uri	https://dspace.lib.ntua.gr/xmlui/handle/123456789/17132
dc.subject	Bioisosteric inhibition	en
dc.subject	Glycogen phosphorylase	en
dc.subject	N-acetyl-β-D- glucopyranosylamine	en
dc.subject	N-trifluoroacetyl-β-D-glucopyranosylamine	en
dc.subject	Type 2 diabetes	en
dc.subject	X-ray crystallography	en
dc.subject.other	enzyme inhibitor	en
dc.subject.other	glycogen phosphorylase	en
dc.subject.other	n acetyl beta dextro glucopyranosylamine	en
dc.subject.other	n trifluoroacetyl beta dextro glucopyranosylamine	en
dc.subject.other	unclassified drug	en
dc.subject.other	water	en
dc.subject.other	article	en
dc.subject.other	catalysis	en
dc.subject.other	chemical interaction	en
dc.subject.other	conformation	en
dc.subject.other	crystallography	en
dc.subject.other	drug structure	en
dc.subject.other	structure analysis	en
dc.subject.other	Crystallography	en
dc.subject.other	Enzyme Inhibitors	en
dc.subject.other	Glucosamine	en
dc.subject.other	Glycogen Phosphorylase	en
dc.subject.other	Models, Molecular	en
dc.subject.other	Muscles	en
dc.title	Crystallographic studies on two bioisosteric analogues, N-acetyl-β-D-glucopyranosylamine and N-trifluoroacetyl-β-D- glucopyranosylamine, potent inhibitors of muscle glycogen phosphorylase	en
heal.type	journalArticle	en
heal.identifier.primary	10.1016/j.bmc.2005.08.010	en
heal.identifier.secondary	http://dx.doi.org/10.1016/j.bmc.2005.08.010	en
heal.publicationDate	2006	en
heal.abstract	Structure-based inhibitor design has led to the discovery of a number of potent inhibitors of glycogen phosphorylase b (GPb), N-acyl derivatives of β-d-glucopyranosylamine, that bind at the catalytic site of the enzyme. The first good inhibitor in this class of compounds, N-acetyl-β-d- glucopyranosylamine (NAG) (Ki = 32 μM), has been previously characterized by biochemical, biological and crystallographic experiments at 2.3 Å resolution. Bioisosteric replacement of the acetyl group by trifluoroacetyl group resulted in an inhibitor, N-trifluoroacetyl-β-d- glucopyranosylamine (NFAG), with a Ki = 75 μM. To elucidate the structural basis of its reduced potency, we determined the ligand structure in complex with GPb at 1.8 Å 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 Å). 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. © 2005 Elsevier Ltd. All rights reserved.	en
heal.journalName	Bioorganic and Medicinal Chemistry	en
dc.identifier.doi	10.1016/j.bmc.2005.08.010	en
dc.identifier.volume	14	en
dc.identifier.issue	1	en
dc.identifier.spage	181	en
dc.identifier.epage	189	en