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|Title:||3 '-Axial CH2OH Substitution on Glucopyranose does not Increase Glycogen Phosphorylase Inhibitory Potency. QM/MM-PBSA Calculations Suggest Why|
Kantsadi, Anastassia L.
Hayes, Joseph M.
Skamnaki, Vicky T.
Zographos, Spyridon E.
Leonidas, Demetres D.
|Type:||Journal Article (Scientific Journal article)|
|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.|
|Journal Title:||Chemical Biology & Drug Design|
|Subject Category:||Science::Biology (General)|
Medicine::Pharmacy and materia medica
|Keywords:||branched C-hydroxymethyl nucleosides; enzyme inhibition; glide docking; glycogen phosphorylase; QM; MM-PBSA; solvation modeling; type 2 diabetes; X-ray crystallography; Chemistry, Medicinal|
|Other Identifiers:||DOI: http://dx.doi.org/10.1111/j.1747-0285.2012.01349.x|
|Rights holder:||© WILEY-BLACKWELL|