Wei Hou, Shuning Zhang, Wei Yi, Peixiang Ma, Hongtao Xu 

Trends in Chemistry

https://doi.org/10.1016/j.trechm.2025.08.008

Abstract

DNA-encoded libraries (DELs) have emerged as a critical technology for rapid hit identification in drug discovery. The effectiveness of DEL selection fundamentally depends on the chemical diversity present within the library. As DNA-compatible chemistry plays a central role in expanding both the chemical space and molecular diversity of DELs, this area has seen significant advancements in recent years. Additionally, research in DNA-compatible chemistry and bioconjugation chemistry demonstrates a synergistic relationship. This review focuses on the most recent developments in DNA-compatible chemistry and highlights its expanding applications beyond traditional library construction. Current synthetic challenges are examined, and potential directions for future research and development are explored.