Zoledronate Derivatives as Potential Inhibitors of Uridine Diphosphate-Galactose Ceramide Galactosyltransferase 8: A Combined Molecular Docking and Dynamic Study

Giovanna Pannuzzo, Adriana Carol Eleonora Graziano, Martina Pannuzzo, Marcelo Fabricio Masman, Rosanna Avola, Venera Cardile*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)

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-b-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.
Original languageEnglish
Pages (from-to)1318-1326
Number of pages9
JournalJournal of Neuroscience Research
Volume94
Issue number11
DOIs
Publication statusPublished - Nov-2016

Keywords

  • Krabbe disease
  • ceramide galactosyltransferase
  • substrate deprivation therapy
  • molecular docking
  • molecular dynamics
  • homology modeling
  • GLOBOID-CELL LEUKODYSTROPHY
  • SUBSTRATE-REDUCTION THERAPY
  • CRYSTAL-STRUCTURE
  • UDP-GALACTOSE
  • TWITCHER MICE
  • SCHWANN-CELLS
  • FORCE-FIELD
  • PSI-BLAST
  • ACID
  • EFFICACY

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