3syr | pdb_00003syr
Glycogen phosphorylase b in complex with beta-D-glucopyranonucleoside 5-fluorouracil
Structural highlights
FunctionPYGM_RABIT Phosphorylase is an important allosteric enzyme in carbohydrate metabolism. Enzymes from different sources differ in their regulatory mechanisms and in their natural substrates. However, all known phosphorylases share catalytic and structural properties. Publication Abstract from PubMedGlycogen phosphorylase is a molecular target for the design of potential hypoglycaemic agents. Structure based design pinpointed that the 3'-position of glucopyranose equipped with a suitable group has the potential to form interactions with enzyme's cofactor, 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'-CH(2) OH glucopyranose derivative. Both ligands were found to be low muM inhibitors with K(i) values of 7.9 and 27.1 muM, respectively. X-ray crystallography revealed that the 3'-CH(2) OH glucopyranose substituent is indeed involved in additional molecular interactions with the PLP gamma-phosphate compared to GlcFU. However it is 3.4 times less potent. To elucidate this discovery, docking followed by post-docking Quantum Mechanics/Molecular Mechanics - Poisson Boltzmann 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'-CH(2) OH-substituted glucopyranose derivative out-weigh the enthalpy gains from the extra contacts formed. The benefits of performing post-docking calculations employing a more accurate solvation model and the QM/MM-PBSA methodology in lead optimization is therefore highlighted, specifically when the role of a highly polar/charged binding interface is significant. (c) 2012 John Wiley & Sons A/S. 3'-axial CH(2) OH substitution on glucopyranose does not increase glycogen phosphorylase inhibitory potency. QM/MM-PBSA calculations suggest why.,Manta S, Xipnitou A, Kiritsis C, Kantsadi AL, Hayes JM, Skamnaki VT, Lamprakis C, Kontou M, Zoumpoulakis P, Zographos SE, Leonidas DD, Komiotis D Chem Biol Drug Des. 2012 Feb 2. doi: 10.1111/j.1747-0285.2012.01349.x. PMID:22296957[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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