In Silico Structural Analysis of Human β-Glucuronidase for Antibody-Drug Conjugates Optimization

Area of Science:

• Biochemistry
• Structural Biology
• Computational Chemistry

Background:

• Human β-glucuronidase (HGUSB) is a lysosomal enzyme crucial for glycosaminoglycan degradation.
• HGUSB's role in cell proliferation and inflammation makes it a therapeutic target, particularly for antibody-drug conjugates (ADCs).
• Optimizing linkers in ADCs is essential for targeted cancer therapies.

Purpose of the Study:

• To investigate the conformational stability of HGUSB with various ligands using computational methods.
• To determine the optimal binding configuration of HGUSB for small molecule interactions.
• To evaluate the binding of β-glucuronic linkers for ADC development.

Main Methods:

• Molecular docking and molecular dynamics (MD) simulations were employed.
• Analysis included substrates, inhibitors, and commercial β-glucuronic linkers.
• Evaluation of binding stoichiometries and conformational stability was performed.

Main Results:

• The maleimide-containing hydrophilic β-glucuronide linker demonstrated the most stable binding to HGUSB.
• A simplified monomeric model of HGUSB was validated for studying macromolecular complexes.
• The study identified optimal binding configurations and interactions for HGUSB.

Conclusions:

• This research provides a structural basis for the recognition mechanism between HGUSB and ADCs.
• The findings support the use of a specific β-glucuronide linker for developing effective β-glucuronic linker-based ADCs.
• The study offers new perspectives for targeted cancer therapies utilizing ADCs.