The X-Chem drug discovery engine is based on a library generated by iterative combinatorial synthesis of small molecules tethered to DNA tags that record the synthetic history of the small molecule.
Every small molecule in the library has a unique DNA barcode attached it. The library is screened as a mixture using affinity-based binding to a target of interest. Certain rare molecules in the library that bind to the target can be “fished out,” while the rest of the molecules wash away. DNA sequencing methods are then used to detect molecules that are enriched when bound to the target. The diverse nature of the library produces multiple families or clusters of related molecules that bind to the target, forming a basis for emergent structure-activity relationships. Structure-activity relationships are typically used by medicinal chemists to guide iterative chemical maturation of a molecule into a drug. Based on the synthetic history encoded in the DNA sequence information, molecules are then made without the DNA tag attached, and tested for activity in conventional assays.
Size and Diversity
Due to the size and diversity of the library, X-Chem can discover multiple series of novel, potent and selective lead compounds at an unprecedented rate of success against a wide range of targets, including some that previously failed using conventional screening methods. A number of proprietary innovations in library design, screening methodology and informatics underlie the exceptional performance of the platform. Those include:
- A superior approach to library construction; allows for additional chemical reactions to become useable in DNA-encoded library synthesis.
- Unique informatics tools show clear direction for pursuing novel series of structures that interact with targets, often at multiple sites on a given target
- Industrial-scale capabilities can process dozens of screening campaigns on a yearly basis
- Output is easily integrated into discovery programs for medicinal chemistry optimization, including structure-based design
Together, these developments result in a much greater repertoire of diversity for small molecules, which cover a range of categories including fragment molecules, small molecular weight heterocyclic compounds, and macrocyclic structures. This diverse library, combined with a heightened ability to detect active molecules, has yielded a robust process that has been highly successful, including against targets categorized as difficult or intractable, such as protein:protein interaction (PPI), ubiquitin ligase, epigenetic and antibacterial targets.