Discovery and Activity Verification of a O-GlcNAc Transferase Inhibitor by Structure-based Virtual Screening

A specific natural-product O-GlcNAc transferase (OGT) inhibitor(Amentoflavone, AF) was identified from a structure-based virtual screening analysis. X-ray structure of the human OGT binding to uridine diphosphate(UDP) was used as the receptor in Discovery Studio 4. 5. AF effectively inhibited OGT in a dose dependent and time dependent manner in vitro. The IC50 value of this compound was 48. 1 mu mol/L. Western blot showed that O-GlcNAc modification of Nup62 by OGT in a cell free reaction system was decreased along with a shift in molecular weight by AF treatment. Furthermore, AF reduced global O-GlcNAcylation in a dose and time-dependent manner in Cos7 cells. Molecular dynamics analysis suggested that AF might form multiple hydrogens bonds with OGT in the same positions as the sugar donor UDP. This study validated the use of structure-based molecular docking to discover novel inhibitors of OGT. AF may be employed as a useful scaffold for the development of more potent OGT inhibitors in the future.