title: Glycogen phosphorylase as a target for type 2 diabetes: synthetic, biochemical, structural and computational evaluation of novel N-acyl-N´-(β-D-glucopyranosyl) urea inhibitors.
abstract: Glycogen phosphorylase (GP), a validated target for the development of anti-hyperglycaemic agents, has been targeted for the design of novel glycopyranosylamine inhibitors. Exploiting the two most potent inhibitors from our previous study of N-acyl-β-D-glucopyranosylamines (Parmenopoulou et al., Bioorg. Med. Chem. 2014, 22, 4810), we have extended the linking group to -NHCONHCO- between the glucose moiety and the aliphatic/aromatic substituent in the GP catalytic site β-cavity. The N-acyl-N´-(β-D-glucopyranosyl) urea inhibitors were synthesized and their efficiency assessed by biochemical methods, revealing inhibition constant values of 4.95 µM and 2.53 µM. Crystal structures of GP in complex with these inhibitors were determined and analyzed, providing data for further structure based design efforts. A novel Linear Response - Molecular Mechanics Coulomb Surface Area (LR-MM-CBSA) method has been developed which relates predicted and experimental binding free energies for a training set of N-acyl-N´-(β-D-glucopyranosyl) urea ligands with a correlation coefficient R(2) of 0.89 and leave-one-out cross-validation (LOO-cv) Q(2) statistic of 0.79. The method has significant applications to direct future lead optimization studies, where ligand entropy loss on binding is revealed as a key factor to be considered. ADMET property predictions revealed that apart from potential permeability issues, the synthesized N-acyl-N´-(β-D-glucopyranosyl) urea inhibitors have drug-like potential without any toxicity warnings.
authors.forename: Anastassia L
authors.initials: AL
authors.lastname: Kantsadi
authors.forename: Vanessa
authors.initials: V
authors.lastname: Parmenopoulou
authors.forename: Dimitar N
authors.initials: DN
authors.lastname: Bakalov
authors.forename: Laura
authors.initials: L
authors.lastname: Snelgrove
authors.forename: George A
authors.initials: GA
authors.lastname: Stravodimos
authors.forename: Demetra S M
authors.initials: DS
authors.lastname: Chatzileontiadou
authors.forename: Stella
authors.initials: S
authors.lastname: Manta
authors.forename: Angeliki
authors.initials: A
authors.lastname: Panagiotopoulou
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Hayes
authors.affiliation: Department of Biochemistry and Biotechnology, University of Thessaly, Ploutonos 26, Larissa, Greece. dkom@bio.uth.gr.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Komiotis
authors.forename: Demetres D
authors.initials: DD
authors.lastname: Leonidas
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D019295:Computational Biology; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000201:enzymology; D005947:Glucose / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors*; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008024:Ligands; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D018482:Muscle, Skeletal / Q000201:enzymology; D011485:Protein Binding; D011817:Rabbits; D012709:Serum Albumin / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D007004:Hypoglycemic Agents; D008024:Ligands; C455275:N-acetyl-N'-glucopyranosylurea; D012709:Serum Albumin; D014508:Urea; D024981:Glycogen Phosphorylase; D005947:Glucose