Dynamic combinatorial chemistry directed by proteins and nucleic acids: a powerful tool for drug discovery.

Protein-directed dynamic combinatorial chemistry (P-D DCC) is a powerful strategy for identifying ligands to protein targets of pharmacological significance. It leverages a thermodynamic templated effect, where proteins selectively amplify high-affinity binders. In contrast, although nucleic acids play critical roles in gene regulation and disease and offer significant therapeutic potential, they remain underexplored in drug discovery. While P-D DCC has been widely applied, the use of nucleic acid-directed dynamic combinatorial chemistry (NA-D DCC) is relatively limited. Expanding these methodologies is essential for tackling emerging infectious diseases and advancing therapeutic development. This review examines the applications, experimental design considerations, recent advancements, and P-D DCC and NA-D DCC perspectives.