Strategy for Designing Selective Lysosomal Acid α-Glucosidase Inhibitors: Binding Orientation and Influence on Selectivity

Atsushi Kato*, Izumi Nakagome, Mizuki Hata, Robert J. Nash, George W.J. Fleet, Yoshihiro Natori, Yuichi Yoshimura, Isao Adachi, Shuichi Hirono

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Citations (SciVal)
162 Downloads (Pure)

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.

Original languageEnglish
Article number2843
Number of pages13
JournalMolecules
Volume25
Issue number12
DOIs
Publication statusPublished - 19 Jun 2020

Keywords

  • Drug design
  • ER α-glucosidase II
  • Glucosidase inhibitor
  • Iminosugars
  • Ligand docking
  • Lysosomal acid α-glucosidase
  • Molecular dynamics
  • alpha-Glucosidases/chemistry
  • Antiviral Agents/chemistry
  • Humans
  • Glycoside Hydrolase Inhibitors/chemistry
  • Imino Sugars/chemistry
  • Drug Design
  • Molecular Docking Simulation
  • 1-Deoxynojirimycin/chemistry
  • Glucosamine/analogs & derivatives

Fingerprint

Dive into the research topics of 'Strategy for Designing Selective Lysosomal Acid α-Glucosidase Inhibitors: Binding Orientation and Influence on Selectivity'. Together they form a unique fingerprint.

Cite this