Enhancing the Small-Scale Screenable Biological Space beyond Known Chemogenomics Libraries with Gray Chemical...

Area of Science:

• Drug Discovery
• Cheminformatics
• Chemical Biology

Background:

• Phenotypic assays are crucial for drug discovery but are limited by complexity and cost.
• Current screening often uses small, well-characterized compound libraries, restricting the search for novel mechanisms of action (MoAs).

Purpose of the Study:

• To develop a cheminformatics approach for identifying compounds with novel MoAs for throughput-limited phenotypic assays.
• To expand the MoA search space beyond traditional chemogenomics libraries.

Main Methods:

• Mining large-scale phenotypic high-throughput screening (HTS) data.
• Identifying chemotypes with cross-assay selectivity and broad structure-activity relationships (SAR).
• Validating findings using cellular profiling assays (Cell Painting, DRUG-seq, Promotor Signature Profiling) and chemical proteomics.

Main Results:

• The approach successfully identified a small set of compounds with likely novel MoAs.
• Compounds exhibited selectivity across multiple assays and broad SAR.
• Validation experiments showed compounds biased toward novel protein targets compared to known libraries.

Conclusions:

• The developed cheminformatics strategy effectively identifies compounds with novel MoAs for phenotypic screening.
• A public compound set has been curated and made available to facilitate research and collaboration.
• This approach enhances the utility of throughput-limited phenotypic assays in drug discovery.