title: Structure based inhibitor design targeting glycogen phosphorylase B. Virtual screening, synthesis, biochemical and biological assessment of novel N-acyl-β-d-glucopyranosylamines.
abstract: Glycogen phosphorylase (GP) is a validated target for the development of new type 2 diabetes treatments. Exploiting the Zinc docking database, we report the in silico screening of 1888 N-acyl-β-d-glucopyranosylamines putative GP inhibitors differing only in their R groups. CombiGlide and GOLD docking programs with different scoring functions were employed with the best performing methods combined in a 'consensus scoring' approach to ranking of ligand binding affinities for the active site. Six selected candidates from the screening were then synthesized and their inhibitory potency was assessed both in vitro and ex vivo. Their inhibition constants' values, in vitro, ranged from 5 to 377μM while two of them were effective at causing inactivation of GP in rat hepatocytes at low μM concentrations. The crystal structures of GP in complex with the inhibitors were defined and provided the structural basis for their inhibitory potency and data for further structure based design of more potent inhibitors.
authors.affiliation: Laboratory of Bio-Organic Chemistry, Department of Biochemistry and Biotechnology, University of Thessaly, 26 Ploutonos Str., 41221 Larissa, Greece.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Parmenopoulou
authors.affiliation: Laboratory of Bio-Organic Chemistry, Department of Biochemistry and Biotechnology, University of Thessaly, 26 Ploutonos Str., 41221 Larissa, Greece.
authors.forename: Anastassia L
authors.initials: AL
authors.lastname: Kantsadi
authors.affiliation: Laboratory of Bio-Organic Chemistry, Department of Biochemistry and Biotechnology, University of Thessaly, 26 Ploutonos Str., 41221 Larissa, Greece.
authors.forename: Vicky G
authors.initials: VG
authors.lastname: Tsirkone
authors.affiliation: Laboratory of Bio-Organic Chemistry, Department of Biochemistry and Biotechnology, University of Thessaly, 26 Ploutonos Str., 41221 Larissa, Greece.
authors.forename: Demetra S M
authors.initials: DS
authors.lastname: Chatzileontiadou
authors.affiliation: Laboratory of Bio-Organic Chemistry, Department of Biochemistry and Biotechnology, University of Thessaly, 26 Ploutonos Str., 41221 Larissa, Greece.
authors.forename: Stella
authors.initials: S
authors.lastname: Manta
authors.affiliation: Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
authors.forename: Spyros E
authors.initials: SE
authors.lastname: Zographos
authors.affiliation: Laboratory of Bio-Organic Chemistry, Department of Biochemistry and Biotechnology, University of Thessaly, 26 Ploutonos Str., 41221 Larissa, Greece.
authors.forename: Christina
authors.initials: C
authors.lastname: Molfeta
authors.affiliation: Department of Physics, University of Cyprus, Nicosia, Cyprus.
authors.forename: Georgios
authors.initials: G
authors.lastname: Archontis
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Loranne
authors.initials: L
authors.lastname: Agius
authors.affiliation: Centre for Materials Science, Division of Chemistry, University of Central Lancashire, Preston PR1 2HE, UK. Electronic address: jhayes@uclan.ac.uk.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Hayes
authors.affiliation: Laboratory of Bio-Organic Chemistry, Department of Biochemistry and Biotechnology, University of Thessaly, 26 Ploutonos Str., 41221 Larissa, Greece. Electronic address: ddleonidas@bio.uth.gr.
authors.forename: Demetres D
authors.initials: DD
authors.lastname: Leonidas
authors.affiliation: Laboratory of Bio-Organic Chemistry, Department of Biochemistry and Biotechnology, University of Thessaly, 26 Ploutonos Str., 41221 Larissa, Greece. Electronic address: dkom@bio.uth.gr.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Komiotis
mesh_terms: D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005944:Glucosamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D025001:Glycogen Phosphorylase, Liver Form / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D025001:Glycogen Phosphorylase, Liver Form; D005944:Glucosamine
keywords: Consensus scoring; Diabetes type 2; Glycogen metabolism; Glycogen phosphorylase; Inhibitor; N-Acyl-β-d-glucopyranosylamines; Virtual screening; X-ray crystallography