Functional Group Transformations (FGTs) for DNA-Encoded Libraries

DNA-encoded libraries (DELs) have transformed early-stage drug discovery by enabling the rapid screening of vast chemical spaces through affinity selection. However, their structural diversity and functional complexity remain constrained by the limited scope of DNA-compatible reactions and the reliance on prefunctionalized building blocks. Functional group transformations (FGTs) have emerged as a versatile yet underexplored strategy for expanding the synthetic capabilities of DELs beyond conventional building-block-driven assembly. By selectively controlling functional-group reactivity, converting readily available functionalities into alternative synthetic handles, and directly remodeling preassembled molecules, FGTs enable molecular diversification at multiple stages of DEL synthesis. In this Review, we present a conceptual framework for on-DNA FGTs based on three complementary synthetic roles: reaction control through functional-group unmasking, chemical-space expansion through functional group interconversion, and function-oriented molecular editing through late-stage functionalization. Together, these strategies highlight how FGTs can extend DEL synthesis toward more programmable and function-oriented molecular diversification.