Design of DNA Encoded Libraries for Medicinal Chemistry

DNA-encoded libraries (DELs) have revolutionized hit identification in drug discovery by offering an accessible, versatile, and cost-effective alternative to traditional high-throughput screening (HTS). This perspective analyzes the results of recent DEL technology (DELT) screens (2020-2025) to enable medicinal chemistry programs, focusing on case studies where active series were generated from DEL, and distills key learnings and design principles for productive library construction. A notable trend is the productivity of 2-cycle DELs, which, despite their smaller size, consistently yield hits and have superior physicochemical properties, compared to 3-cycle libraries.