title: Zoledronate derivatives as potential inhibitors of uridine diphosphate-galactose ceramide galactosyltransferase 8: A combined molecular docking and dynamic study.
abstract: Krabbe's disease is a neurodegenerative disorder caused by deficiency of galactocerebrosidase activity that affects the myelin sheath of the nervous system, involving dysfunctional metabolism of sphingolipids. It has no cure. Because substrate inhibition therapy has been shown to be effective in some human lysosomal storage diseases, we hypothesize that a substrate inhibition therapeutic approach might be appropriate to allow correction of the imbalance between formation and breakdown of glycosphingolipids and to prevent pathological storage of psychosine. The enzyme responsible for the biosynthesis of galactosylceramide and psychosine is uridine diphosphate-galactose ceramide galactosyltransferase (2-hydroxyacylsphingosine 1-β-galactosyltransferase; UGT8; EC 2.4.1.45), which catalyzes the transferring of galactose from uridine diphosphate-galactose to ceramide or sphingosine, an important step of the biosynthesis of galactosphingolipids. Because some bisphosphonates have been identified as selective galactosyltransferase inhibitors, we verify the binding affinity to a generated model of the enzyme UGT8 and investigate the molecular mechanisms of UGT8-ligand interactions of the bisphosphonate zoledronate by a multistep framework combining homology modeling, molecular docking, and molecular dynamics simulations. From structural information on UGTs' active site stereochemistry, charge density, and access through the hydrophobic environment, the molecular docking procedure allowed us to identify zoledronate as a potential inhibitor of human ceramide galactosyltransferase. More importantly, zoledronate derivates were designed through computational modeling as putative new inhibitors. Experiments in vivo and in vitro have been planned to verify the possibility of using zoledronate and/or the newly identified inhibitors of UGT8 for a substrate inhibition therapy useful for treatment of Krabbe's disease and/or other lysosomal disorders. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Pannuzzo
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania, Italy.
authors.forename: Adriana Carol Eleonora
authors.initials: AC
authors.lastname: Graziano
authors.affiliation: Department of Computational Biology, Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Pannuzzo
authors.affiliation: Department of Biocatalysis and Biotransformation, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands.
authors.forename: Marcelo Fabricio
authors.initials: MF
authors.lastname: Masman
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Avola
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania, Italy. cardile@unict.it.
authors.forename: Venera
authors.initials: V
authors.lastname: Cardile
mesh_terms: D000818:Animals; D004164:Diphosphonates / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051147:Ganglioside Galactosyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D004791:Enzyme Inhibitors; D007093:Imidazoles; D000077211:Zoledronic Acid; C511211:UGT8 protein, human; D051147:Ganglioside Galactosyltransferase
keywords: Krabbe disease; ceramide galactosyltransferase; homology modeling; molecular docking; molecular dynamics; substrate deprivation therapy