3SYM

Glycogen Phosphorylase b in complex with 3 -C-(hydroxymethyl)-beta-D-glucopyranonucleoside of 5-fluorouracil

Summary for 3SYM

• Entry DOI: 10.2210/pdb3sym/pdb
• Related: 3SYR
• Descriptor: Glycogen phosphorylase, muscle form, 5-fluoro-1-[3-C-(hydroxymethyl)-beta-D-glucopyranosyl]pyrimidine-2,4(1H,3H)-dione (3 entities in total)
• Functional Keywords: alpha and beta protein, transferase-transferase inhibitor complex, muscle, transferase, glycogen metabolism, transferase/transferase inhibitor
• Biological source: Oryctolagus cuniculus (European rabbit,Japanese white rabbit,domestic rabbit,rabbits)
• Total number of polymer chains: 1
• Total formula weight: 97841.56

Authors

Skamnaki, V.T.,Katsandi, A.L.,Kontou, M.,Leonidas, D.D. (deposition date: 2011-07-18, release date: 2012-02-15, Last modification date: 2020-07-29)

Primary citation

Manta, S.,Xipnitou, A.,Kiritsis, C.,Kantsadi, A.L.,Hayes, J.M.,Skamnaki, V.T.,Lamprakis, C.,Kontou, M.,Zoumpoulakis, P.,Zographos, S.E.,Leonidas, D.D.,Komiotis, D.
3'-Axial CH(2) OH Substitution on Glucopyranose does not Increase Glycogen Phosphorylase Inhibitory Potency. QM/MM-PBSA Calculations Suggest Why.
Chem.Biol.Drug Des., 79:663-673, 2012

PubMed 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 enzyme's cofactor, pyridoxal 5'-phosphate (PLP), thus enhancing the inhibitory potency. Hence, we have investigated the binding of two ligands, 1-(β-d-glucopyranosyl)5-fluorouracil (GlcFU) and its 3'-CH(2) OH glucopyranose derivative. Both ligands were found to be low micromolar inhibitors with K(i) values of 7.9 and 27.1 μm, respectively. X-ray crystallography revealed that the 3'-CH(2) OH glucopyranose substituent is indeed involved in additional molecular interactions with the PLP γ-phosphate compared with GlcFU. However, it is 3.4 times less potent. To elucidate this discovery, docking followed by postdocking 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 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.

PubMed: 22296957
DOI: 10.1111/j.1747-0285.2012.01349.x

Experimental method

X-RAY DIFFRACTION (2.4 Å)