Novel selection methods for DNA-encoded chemical libraries

• DNA-encoded chemical libraries are a source of diverse bioactive compounds.
• Current approaches enable one-pot evaluation of all library members.
• New methods evaluate libraries against one or more unmodified target proteins.
• Related approaches have enabled DNA-encoded reaction discovery.
• New DNA-based approaches for detecting protein interactions could be adapted to small-molecule discovery.

Driven by the need for new compounds to serve as biological probes and leads for therapeutic development and the growing accessibility of DNA technologies including high-throughput sequencing, many academic and industrial groups have begun to use DNA-encoded chemical libraries as a source of bioactive small molecules. In this review, we describe the technologies that have enabled the selection of compounds with desired activities from these libraries. These methods exploit the sensitivity of in vitro selection coupled with DNA amplification to overcome some of the limitations and costs associated with conventional screening methods. In addition, we highlight newer techniques with the potential to be applied to the high-throughput evaluation of DNA-encoded chemical libraries.