Trends in Hit-to-Lead Optimization Following DNA-Encoded Library Screens

DNA-encoded library (DEL) screens have emerged as a powerful hit-finding tool for a number of biological targets. In this Innovations article, we review published hit-to-lead optimization studies following DEL screens. Trends in molecular property changes from hit to lead are identified, and specific optimization tactics are exemplified in case studies. Across the studies, physicochemical property and structural changes post-DEL screening are similar to those which occur during hit-to-lead optimization following high throughputscreens (HTS). However, unique aspects of DEL-the combinatorial synthetic methods which enable DEL synthesis and the linker effects at the DNA attachment point-impact the strategies and outcomes of hit-to-lead optimizations.

Automated summary

DNA-encoded library (DEL) screens are a powerful tool for hit-finding in biological targets, and studies have shown that the molecular property changes post-DEL screening are similar to those in hit-to-lead optimization following high throughput screens. Unique aspects of DEL, such as combinatorial synthetic methods and linker effects at the DNA attachment point, impact the strategies and outcomes of hit-to-lead optimizations.