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

Crystallographic studies on two bioisosteric analogues, N-acetyl-b-D-glucopyranosylamine and N-trifluoroacetyl-b-D-glucopyranosylamine, potent inhibitors of muscle glycogen phosphorylase
Crystallographic studies on two bioisosteric analogues, N-acetyl-b-D-glucopyranosylamine and N-trifluoroacetyl-b-D-glucopyranosylamine, potent inhibitors of muscle glycogen phosphorylase
Structure-based inhibitor design has led to the discovery of a number of potent inhibitors of glycogen phosphorylase b GPb), N-acyl derivatives of b-D-glucopyranosylamine, that bind at the catalytic site of the enzyme. The first good inhibitor in this class of compounds, N-acetyl-b-D-glucopyranosylamine NAG)(Ki = 32 lM), 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-b-D-glucopyranosylamine (NFAG), with a Ki = 75 lM. 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.
0968-0896
181-189
Anagnostou, Eleni
4527c274-f765-44ce-89ab-0e437aa3d870
Kosmopoulou, Magda N.
d399ed89-fcea-4944-b593-b249996b26a9
Chrysina, Evangelia D.
f31bea4c-6bed-412c-8d48-ac488491244c
Leonidas, Demetres D.
4e7e8a61-a92f-496e-a929-473cd16c1632
Hadjiloi, Theodoros
39f7de83-24ea-4593-9a7e-f175cadb53d8
Tiraidis, Costantinos
64eac703-b72e-4c21-8fdf-72661f1adfab
Zographos, Spyros E.
da79d6c9-e7c0-49c0-8877-300b4ae09e50
Györgydeák, Zoltan
9d64b0d3-2213-4c13-b5d3-9bc2afbf2010
Somsák, Laszlo
4b05f33a-d7f1-4de7-a15c-fea20b89f3d0
Docsa, Tibor
a9446888-5bf1-48d9-a6ad-338db6a9c744
Gergely, Pal
4f700ef8-d1a7-4d05-bb7d-5522d755bb0a
Kolisis, Fragiskos N.
6798fc21-15bd-4eeb-b17b-7c04f86ccc78
Oikonomakos, Nikos G.
5107d56a-a43d-4d51-94ab-98484c861120
Anagnostou, Eleni
4527c274-f765-44ce-89ab-0e437aa3d870
Kosmopoulou, Magda N.
d399ed89-fcea-4944-b593-b249996b26a9
Chrysina, Evangelia D.
f31bea4c-6bed-412c-8d48-ac488491244c
Leonidas, Demetres D.
4e7e8a61-a92f-496e-a929-473cd16c1632
Hadjiloi, Theodoros
39f7de83-24ea-4593-9a7e-f175cadb53d8
Tiraidis, Costantinos
64eac703-b72e-4c21-8fdf-72661f1adfab
Zographos, Spyros E.
da79d6c9-e7c0-49c0-8877-300b4ae09e50
Györgydeák, Zoltan
9d64b0d3-2213-4c13-b5d3-9bc2afbf2010
Somsák, Laszlo
4b05f33a-d7f1-4de7-a15c-fea20b89f3d0
Docsa, Tibor
a9446888-5bf1-48d9-a6ad-338db6a9c744
Gergely, Pal
4f700ef8-d1a7-4d05-bb7d-5522d755bb0a
Kolisis, Fragiskos N.
6798fc21-15bd-4eeb-b17b-7c04f86ccc78
Oikonomakos, Nikos G.
5107d56a-a43d-4d51-94ab-98484c861120

Anagnostou, Eleni, Kosmopoulou, Magda N., Chrysina, Evangelia D., Leonidas, Demetres D., Hadjiloi, Theodoros, Tiraidis, Costantinos, Zographos, Spyros E., Györgydeák, Zoltan, Somsák, Laszlo, Docsa, Tibor, Gergely, Pal, Kolisis, Fragiskos N. and Oikonomakos, Nikos G. (2006) Crystallographic studies on two bioisosteric analogues, N-acetyl-b-D-glucopyranosylamine and N-trifluoroacetyl-b-D-glucopyranosylamine, potent inhibitors of muscle glycogen phosphorylase. Bioorganic & Medicinal Chemistry, 14, 181-189. (doi:10.1016/j.bmc.2005.08.010).

Record type: Article

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 b-D-glucopyranosylamine, that bind at the catalytic site of the enzyme. The first good inhibitor in this class of compounds, N-acetyl-b-D-glucopyranosylamine NAG)(Ki = 32 lM), 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-b-D-glucopyranosylamine (NFAG), with a Ki = 75 lM. 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.

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Published date: 2006
Organisations: Geochemistry

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Local EPrints ID: 339954
URI: http://eprints.soton.ac.uk/id/eprint/339954
ISSN: 0968-0896
PURE UUID: 346084ee-3a6f-4960-ac69-050127052d70

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Date deposited: 06 Jun 2012 12:47
Last modified: 02 Dec 2019 20:57

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Contributors

Author: Eleni Anagnostou
Author: Magda N. Kosmopoulou
Author: Evangelia D. Chrysina
Author: Demetres D. Leonidas
Author: Theodoros Hadjiloi
Author: Costantinos Tiraidis
Author: Spyros E. Zographos
Author: Zoltan Györgydeák
Author: Laszlo Somsák
Author: Tibor Docsa
Author: Pal Gergely
Author: Fragiskos N. Kolisis
Author: Nikos G. Oikonomakos

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