3′-Axial CH2OH Substitution on Glucopyranose does not Increase Glycogen Phosphorylase Inhibitory Potency. QM/MM-PBSA Calculations Suggest Why

摘要: Glycogen phosphorylase is a molecular target for the design of potential hypoglycemic agents. Structure-based pinpointed that 3′-position glucopyranose equipped with suitable group has to form interactions enzyme’s cofactor, pyridoxal 5′-phosphate (PLP), thus enhancing inhibitory potency. Hence, we have investigated binding two ligands, 1-(β-d-glucopyranosyl)5-fluorouracil (GlcFU) and its 3′-CH2OH derivative. Both ligands were found be low micromolar inhibitors Ki values 7.9 27.1 μm, respectively. X-ray crystallography revealed substituent indeed involved in additional PLP γ-phosphate compared GlcFU. However, it 3.4 times less potent. To elucidate this discovery, docking followed by postdocking Quantum Mechanics/Molecular Mechanics – Poisson–Boltzmann Surface Area (QM/MM-PBSA) affinity calculations performed. While predictions failed reflect kinetic results, QM/MM-PBSA desolvation energy cost 3′-CH2OH-substituted derivative out-weigh enthalpy gains from extra contacts formed. The benefits performing employing more accurate solvation model methodology lead optimization are therefore highlighted, specifically when role highly polar/charged interface significant.