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

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Enzymology

Background:

• Deoxynojirimycin (DNJ) derivatives inhibit α-glucosidases, showing therapeutic potential for diabetes, viral infections, and genetic disorders.
• Achieving selectivity among various α-glucosidases is challenging due to subtle differences in sugar-recognition sites, limiting drug development.
• Targeting specific enzyme pockets, like the alkyl chain storage site, offers a novel strategy for selective inhibitor design.

Purpose of the Study:

• To develop a selective inhibitor for lysosomal acid α-glucosidase (GAA) by focusing on the enzyme's alkyl chain storage site.
• To design and synthesize a novel iminosugar derivative with enhanced selectivity for GAA.
• To investigate the molecular interactions and binding characteristics of the designed inhibitor.

Main Methods:

• Design of α-1-C-heptyl-1,4-dideoxy-1,4-imino-l-arabinitol (LAB) based on targeting the alkyl chain storage site of GAA.
• In vitro inhibition assays to determine the potency (IC50) and selectivity (selectivity index) of the designed inhibitor.
• Molecular dynamic (MD) simulations to analyze ligand-binding conformation stability and interactions.
• Molecular docking studies to assess binding feasibility with other α-glucosidases, such as ER α-glucosidase II.

Main Results:

• The synthesized compound, α-1-C-heptyl-LAB, potently inhibited GAA with an IC50 of 0.44 µM.
• The inhibitor demonstrated remarkable selectivity for GAA, with a selectivity index of 168.2.
• MD simulations indicated improved binding stability with increasing alkyl chain length, revealing specific hydrophobic interactions with GAA residues (Trp481, Phe525, Met519).
• Molecular docking suggested that ER α-glucosidase II lacks sufficient space for the long alkyl chain, confirming selectivity.

Conclusions:

• The design strategy focusing on the alkyl chain storage site enables the creation of highly selective GAA inhibitors.
• α-1-C-heptyl-LAB represents a promising lead compound for developing targeted therapies for GAA-related disorders.
• Exploiting enzyme-specific pocket shapes and hydrophobic interactions is a viable approach for designing selective enzyme inhibitors.