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, 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	2014-03-01T01:55:31Z
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