title: The binding of C5-alkynyl and alkylfurano[2,3-d]pyrimidine glucopyranonucleosides to glycogen phosphorylase b: synthesis, biochemical and biological assessment.
abstract: C5-alkynyl and alkylfurano[2,3-d]pyrimidine glucopyranonucleosides have been synthesized and studied as inhibitors of glycogen phosphorylase b (GPb). Kinetic experiments have shown that most of these compounds were low micromolar inhibitors of the enzyme. The best inhibitor was 1-(β-D-glucopyranosyl)-5-ethynyluracil (K(i)=4.7 μM). Crystallographic analysis of these compounds in complex with GPb revealed that inhibitors with a long C5-alkynyl group exploited interactions with β-pocket of the active site and induced significant conformational changes of the 280s loop compared to GPb in complex with compounds with a short C5-alkynyl group. The results highlight the importance in the length of the aliphatic groups used to enhance inhibitory potency for the exploitation of the hydrophobic β-pocket. The best of the inhibitors had also a moderate effect on glycogenolysis in the cellular lever with an IC(50) value of 291.4 μM.
authors: Department of Biochemistry and Biotechnology, University of Thessaly, 26 Ploutonos Str. 41221 Larissa, Greece.
authors: A L
authors: AL
authors: Kantsadi
authors: S
authors: S
authors: Manta
authors: A-M G
authors: AM
authors: Psarra
authors: A
authors: A
authors: Dimopoulou
authors: C
authors: C
authors: Kiritsis
authors: V
authors: V
authors: Parmenopoulou
authors: V T
authors: VT
authors: Skamnaki
authors: P
authors: P
authors: Zoumpoulakis
authors: S E
authors: SE
authors: Zographos
authors: D D
authors: DD
authors: Leonidas
authors: D
authors: D
authors: Komiotis
mesh_terms: D000480:Alkynes / Q000737:chemistry*; D000818:Animals; D020134:Catalytic Domain; D060326:Chemistry Techniques, Synthetic; D024981:Glycogen Phosphorylase / Q000737:chemistry / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D011817:Rabbits
chemical_list: D000480:Alkynes; D007004:Hypoglycemic Agents; D011741:Pyrimidine Nucleosides; D024981:Glycogen Phosphorylase