In a review article published in Angewandte Chemie International Edition, a research group led by LU Xiaojie from the Shanghai Institute of Materia Medica (SIMM) of the Chinese Academy of Sciences highlighted rational construction strategies of DNA-encoded chemical libraries for drug discovery.

Fragment-based DNA-encoded library (DEL) strategies introduce minimal structural fragments with broad chemical space coverage into DNA-encoded libraries, allowing small-molecule ligands to efficiently probe multiple binding sub-sites of a target. Through fragment growing, merging, or linking approaches, ligands with high affinity and selectivity can be rapidly generated within the DEL framework. These strategies not only enhance structural diversity during screening but also provide abundant starting points for subsequent structure optimization.

The covalent DEL strategy incorporates electrophilic warheads such as acrylamides or sulfonyl fluorides to enable irreversible covalent modification of specific target residues, particularly cysteines. It strengthens binding stability between compounds and proteins while also capturing transient or low-affinity interactions, thereby broadening the applicability of DEL technology to otherwise "undruggable" targets. The emergence of covalent DELs signifies a conceptual shift in screening from simply "binding" to effectively "occupying" functional sites.

Focused DEL strategies emphasize the design of targeted sub-libraries around specific protein families, functional domains, or binding motifs. By integrating structural insights, ligand preferences, and biological context, these sub-libraries often deliver higher hit rates and superior hit quality, exemplifying the transition of DEL technology from broad, random exploration to precise and rational targeting.

In summary, DELs are undergoing a pivotal transformation from quantity-driven to quality-driven discovery. The conceptual innovation of library design stands at the heart of this shift. With the continual advancement of fragment-based strategies, covalent targeting, and focused library construction, DELs are poised to unlock greater potential in multi-target drug discovery, intervention of previously intractable proteins, and molecular probe development.