Computational framework for discovering small molecule ligands targeting lysosomal proteins

Overview

This solution is a computational drug discovery framework that screens large compound libraries against lysosomal enzymes to identify small molecules capable of binding to and stabilizing these proteins. The platform addresses critical unmet needs in lysosomal storage disorders, such as Sanfilippo syndrome types A and B, where mutations in enzymes like Heparan-N-sulfatase (SGSH) and N-acetyl-α-glucosaminidase (NAGLU) cause progressive disease. By identifying compounds that act as pharmacological chaperones—small molecules that help misfolded proteins regain proper function—the technology offers a pathway to novel therapeutics. Additionally, the framework supports the design of fragments that can be modified to incorporate PET (positron emission tomography) ligands, enabling diagnostic imaging of lysosomal protein activity.

Technical specifications

Key features:

• Molecular docking-based virtual screening against crystal structures of lysosomal enzymes, including SGSH, NAGLU, and N-acetylgalactosamine-4-sulfatase (IDS)
• Validated screening pipeline that has successfully narrowed over 8,800 compounds down to 10 high-priority candidates for SGSH and NAGLU, now undergoing in vitro testing
• Fragment-based optimization approach for refining initial hits into more potent and selective compounds
• Atomistic modeling of protein–glycosaminoglycan (GAG) interactions, building on prior work with COVID-19 proteins and heparanase
• Compatibility with glycomimetic design for rational development of inhibitory compounds
• Extensible architecture applicable to any lysosomal protein with an available X-ray structure, including mutant variants

Technology readiness level

The framework has been validated through initial virtual screening campaigns against SGSH and NAGLU, with 10 candidate compounds currently being tested in vitro. A collaboration with a chemistry group (Prof. Vito Ferro) has produced synthesized chaperones that are being modeled and optimized. The platform is ready for expanded application across the broader landscape of lysosomal proteins with known crystal structures. Full-scale screening, including evaluation against mutant proteins and integration of PET ligand modifications, is projected as a two-year research program. Existing collaborations with chemists, crystallographers, and neuroscientists in Australia provide pathways for cellular validation, and the team is actively seeking partnerships for PET imaging expertise and key personnel funding to advance toward translational applications.