Docking study and biological evaluation of pyrrolidine-based iminosugars as pharmacological chaperones for Gaucher disease

Atsushi Kato*, Izumi Nakagome, Kasumi Sato, Arisa Yamamoto, Isao Adachi, Robert J. Nash, George W.J. Fleet, Yoshihiro Natori, Yasuka Watanabe, Tatsushi Imahori, Yuichi Yoshimura, Hiroki Takahata, Shuichi Hirono

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

We report on the synthesis and biological evaluation of a series of α-1-C-alkylated 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) derivatives as pharmacological chaperones for Gaucher disease. The parent compound, DAB, did not show inhibition of human β-glucocerebrosidase but showed moderate intestinal α-glucosidase inhibition; in contrast, extension of α-1-C-alkyl chain length gave a series of highly potent and selective inhibitors of the β-glucocerebrosidase. Our design of α-1-C-tridecyl-DAB (5j) produced a potent inhibitor of the β-glucocerebrosidase, with IC50 value of 0.77 μM. A molecular docking study revealed that the α-1-C-tridecyl group has a favorable interaction with the hydrophobic pocket and the sugar analogue part (DAB) interacted with essential hydrogen bonds formed to Asp127, Glu235 and Glu340. Furthermore, α-1-C-tridecyl-DAB (5j) displayed enhancement of activity at an effective concentration 10-times lower than isofagomine. α-1-C-Tridecyl-DAB therefore provides the first example of a pyrrolidine iminosugar as a new class of promising pharmacological chaperones with the potential for treatment of Gaucher disease. 2016 The Royal Society of Chemistry.

Original languageEnglish
Pages (from-to)1039-1048
Number of pages10
JournalOrganic and Biomolecular Chemistry
Volume14
Issue number3
DOIs
StatePublished - 2016

ASJC Scopus subject areas

  • Biochemistry
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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