title: 3'-axial CH2 OH substitution on glucopyranose does not increase glycogen phosphorylase inhibitory potency. QM/MM-PBSA calculations suggest why.
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.
authors.affiliation: Department of Biochemistry and Biotechnology, University of Thessaly, 26 Ploutonos Str., Larissa, Greece.
authors.forename: Stella
authors.initials: S
authors.lastname: Manta
authors.forename: Andromachi
authors.initials: A
authors.lastname: Xipnitou
authors.forename: Christos
authors.initials: C
authors.lastname: Kiritsis
authors.forename: Anastassia L
authors.initials: AL
authors.lastname: Kantsadi
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Hayes
authors.forename: Vicky T
authors.initials: VT
authors.lastname: Skamnaki
authors.forename: Christos
authors.initials: C
authors.lastname: Lamprakis
authors.forename: Maria
authors.initials: M
authors.lastname: Kontou
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Zoumpoulakis
authors.forename: Spyridon E
authors.initials: SE
authors.lastname: Zographos
authors.forename: Demetres D
authors.initials: DD
authors.lastname: Leonidas
authors.forename: Dimitri
authors.initials: D
authors.lastname: Komiotis
mesh_terms: D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000201:enzymology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005947:Glucose / Q000031:analogs & derivatives*; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000494:pharmacology*; D056004:Molecular Dynamics Simulation; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D024981:Glycogen Phosphorylase; D005947:Glucose