dc.creator | Manta, S. | en |
dc.creator | Xipnitou, A. | en |
dc.creator | Kiritsis, C. | en |
dc.creator | Kantsadi, A. L. | en |
dc.creator | Hayes, J. M. | en |
dc.creator | Skamnaki, V. T. | en |
dc.creator | Lamprakis, C. | en |
dc.creator | Kontou, M. | en |
dc.creator | Zoumpoulakis, P. | en |
dc.creator | Zographos, S. E. | en |
dc.creator | Leonidas, D. D. | en |
dc.creator | Komiotis, D. | en |
dc.date.accessioned | 2015-11-23T10:38:48Z | |
dc.date.available | 2015-11-23T10:38:48Z | |
dc.date.issued | 2012 | |
dc.identifier | 10.1111/j.1747-0285.2012.01349.x | |
dc.identifier.issn | 1747-0277 | |
dc.identifier.uri | http://hdl.handle.net/11615/30673 | |
dc.description.abstract | Glycogen phosphorylase is a molecular target for the design of potential hypoglycemic agents. Structure-based design pinpointed that the 3'-position of glucopyranose equipped with a suitable group has the potential to form interactions with enzymes cofactor, pyridoxal 5'-phosphate (PLP), thus enhancing the inhibitory potency. Hence, we have investigated the binding of two ligands, 1-(beta-d-glucopyranosyl)5-fluorouracil (GlcFU) and its 3'-CH2OH glucopyranose derivative. Both ligands were found to be low micromolar inhibitors with K-i values of 7.9 and 27.1 mu m, respectively. X-ray crystallography revealed that the 3'-CH2OH glucopyranose substituent is indeed involved in additional molecular interactions with the PLP gamma-phosphate compared with GlcFU. However, it is 3.4 times less potent. To elucidate this discovery, docking followed by postdocking Quantum Mechanics/Molecular Mechanics PoissonBoltzmann Surface Area (QM/MM-PBSA) binding affinity calculations were performed. While the docking predictions failed to reflect the kinetic results, the QM/MM-PBSA revealed that the desolvation energy cost for binding of the 3'-CH2OH-substituted glucopyranose derivative out-weigh the enthalpy gains from the extra contacts formed. The benefits of performing postdocking calculations employing a more accurate solvation model and the QM/MM-PBSA methodology in lead optimization are therefore highlighted, specifically when the role of a highly polar/charged binding interface is significant. | en |
dc.source.uri | <Go to ISI>://WOS:000302296700005 | |
dc.subject | branched C-hydroxymethyl nucleosides | en |
dc.subject | enzyme inhibition | en |
dc.subject | glide docking | en |
dc.subject | glycogen phosphorylase | en |
dc.subject | QM | en |
dc.subject | MM-PBSA | en |
dc.subject | solvation modeling | en |
dc.subject | type 2 | en |
dc.subject | diabetes | en |
dc.subject | X-ray crystallography | en |
dc.subject | PROTEIN-LIGAND COMPLEXES | en |
dc.subject | QUANTUM MECHANICS/MOLECULAR MECHANICS | en |
dc.subject | HEPATIC | en |
dc.subject | GLUCOSE-PRODUCTION | en |
dc.subject | IMPLICIT SOLVATION MODELS | en |
dc.subject | BINDING FREE-ENERGY | en |
dc.subject | ALPHA-D-GLUCOSE | en |
dc.subject | WATER-MOLECULES | en |
dc.subject | T-STATE | en |
dc.subject | PHARMACOLOGICAL INHIBITION | en |
dc.subject | CATALYTIC SITE | en |
dc.subject | Biochemistry & Molecular Biology | en |
dc.subject | Chemistry, Medicinal | en |
dc.title | 3 '-Axial CH2OH Substitution on Glucopyranose does not Increase Glycogen Phosphorylase Inhibitory Potency. QM/MM-PBSA Calculations Suggest Why | en |
dc.type | journalArticle | en |