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 language | English |
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Article number | 2843 |
Number of pages | 13 |
Journal | Molecules |
Volume | 25 |
Issue number | 12 |
DOIs | |
Publication status | Published - 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