Strategy for Designing Selective Lysosomal Acid α-Glucosidase InhibitorsBinding Orientation and Influence on Selectivity

Authors Organisations
  • Atsushi Kato(Author)
    University of Toyama
  • Izumi Nakagome(Author)
    Kitasato University
  • Mizuki Hata(Author)
    University of Toyama
  • Robert Nash(Author)
  • George W.J. Fleet(Author)
    University of Oxford
  • Yoshihiro Natori(Author)
    Tohoku Pharmaceutical University
  • Yuichi Yoshimura(Author)
    Tohoku Pharmaceutical University
  • Isao Adachi(Author)
    University of Toyama
  • Shuichi Hirono(Author)
    Kitasato University
Type Article
Original languageEnglish
Article number2843
Number of pages13
JournalMolecules
Volume25
Issue number12
Early online date19 Jun 2020
DOI
Publication statusE-pub ahead of print - 19 Jun 2020
Links
Handle.net
Show download statistics
View graph of relations
Citation formats

Abstract

Deoxynojirimycin (DNJ) is the archetypal iminosugar, in which the configuration of the hydroxyl groups in the piperidine ring truly mimic those of d-glucopyranose; DNJ and derivatives have beneficial effects as therapeutic agents, such as anti-diabetic and antiviral agents, and pharmacological chaperones for genetic disorders, because they have been shown to inhibit α-glucosidases from various sources. However, attempts to design a better molecule based solely on structural similarity cannot produce selectivity between α-glucosidases that are localized in multiple organs and tissues, because the differences of each sugar-recognition site are very subtle. In this study, we provide the first example of a design strategy for selective lysosomal acid α-glucosidase (GAA) inhibitors focusing on the alkyl chain storage site. Our design of α-1-C-heptyl-1,4-dideoxy-1,4-imino-l-arabinitol (LAB) produced a potent inhibitor of the GAA, with an IC50 value of 0.44 µM. It displayed a remarkable selectivity toward GAA (selectivity index value of 168.2). A molecular dynamic simulation study revealed that the ligand-binding conformation stability gradually improved with increasing length of the α-1-C-alkyl chain. It is noteworthy that α-1-C-heptyl-LAB formed clearly different interactions from DNJ and had favored hydrophobic interactions with Trp481, Phe525, and Met519 at the alkyl chain storage pocket of GAA. Moreover, a molecular docking study revealed that endoplasmic reticulum (ER) α-glucosidase II does not have enough space to accommodate these alkyl chains. Therefore, the design strategy focusing on the shape and acceptability of long alkyl chain at each α-glucosidase may lead to the creation of more selective and practically useful inhibitors.

Keywords

  • Drug design, ER α-glucosidase II, Glucosidase inhibitor, Iminosugars, Ligand docking, Lysosomal acid α-glucosidase, Molecular dynamics

Documents