Chapter 5: On-DNA Medicinal Chemistry: Focused Libraries, Fragment Expansion, and Hit Optimisation

Since their inception thirty years ago, DNA-encoded libraries (DELs) have proven to be a formidable technique for naïve hit finding, with their implementation facilitating the generation of lead-series across a wide range of target classes. In recent years however, it has been demonstrated that the utility of DELs within drug discovery need not be restricted to this purpose, with a variety of strategies being adopted to broaden the impact of encoded libraries within the field. Discussed herein are the current applications of DELs to the wider medicinal chemistry pipeline, including the application and impact of focused libraries; the use of encoded libraries for fragment discovery and expansion; and the potential of DELs for facilitation of hit optimisation processes. The current state of the field is assessed, and potential future directions for the technology within the area are explored.