Virtual screening platform for lysosomal enzyme molecular probes

Overview

This offering provides a virtual screening and hit-to-probe workflow targeting lysosomal enzymes, the proteins responsible for breaking down cellular components within lysosomes. Identifying selective binders for these enzymes creates molecular probes that can be used to study lysosomal activity, supporting research into neurodegeneration, lysosomal storage disorders, and cell biology. The approach combines structural biology, computational chemistry, and biochemical assay validation to deliver tractable starting points for probe development.

The workflow is tailored for targets relevant to the central nervous system by screening against compound collections optimised for blood-brain barrier penetration, expanding the utility of resulting probes for neuroscience applications.

Technical specifications

Screening approach:

• Structure-based virtual screening against solved crystal structures and predicted AlphaFold models of lysosomal enzymes
• Prioritisation of enzymes with commercially available activity or binding assays and those uniquely expressed during lysosomal digestion
• Use of a curated compound collection designed for blood-brain barrier crossing
• Acquisition and biochemical testing of 20–30 compounds per enzyme target
• Follow-up testing of commercially available analogues to generate preliminary structure-activity relationship data

Track record:

• Validated across multiple enzymatic and protein systems using structure-based virtual screening
• Reported hit identification on nine out of ten targets in prior campaigns
• Compatible with a range of assay formats used in biochemical screening

Technology readiness level

The underlying virtual screening methodology is well established through prior application to diverse protein targets, with consistent hit rates reported. The lysosome-specific application is at an early stage, with future work focused on surveying known lysosomal proteins, matching them to available structures, selecting assay-compatible targets, and progressing compounds through purchase and experimental validation to generate confirmed binders and preliminary structure-activity insights.