Design, synthesis, and biological evaluation of iminosugars as pharmacological chaperone for Gaucher disease

  • Kato, Atsushi (PI)
  • Takahata, H. (CoPI)
  • Hirono, Shuichi (CoPI)
  • Ishii, Satoshi (CoPI)
  • Adachi, Isao (CoPI)

Project Details

Description

We report on the identification of the required configuration and binding orientation of iminosugars against b-glucocerebrosidase. A molecular docking study revealed that strong-binding iminosugars had a favorable van der Waals interactions and the hydrogen bonding. Calystegines, which is one of the candidates for pharmacological chaperone, bound into the same active site as isofagomine and the essential hydrogen bonds formed to Asp127, Glu235 and Glu340 were maintained. However, their binding orientations were obviously different. It is noteworthy that Type 1 orientated calystegines effectively stabilized b-glucocerebrosidase, and consequently increased intracellular b-glucocerebrosidase activities in N370S fibroblasts, while Type 2 orientated calystegines could not keep the enzyme activity. These results clearly indicate that the binding orientations of iminosugars are changed by the configuration of the hydroxyl groups.
StatusFinished
Effective start/end date2011/04/012014/03/31

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