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.