Tools for DNA-encoded library synthesis.

DNA-encoded libraries (DELs) are a widely used technology for screening drug-like compounds en masse on biological targets. DEL screens help in assessing the ligandability of biological targets, yielding chemical biology probes, and identifying starting points for clinical drug development. DELs are most often synthesized by combinatorial chemistry routes in homogeneous aqueous solutions to obtain libraries with vast numbers of compounds. Aqueous conditions, the chemical reactivity of the DNA barcode, and the combinatorial workflow limit the synthesis methodology to a few validated DEL synthesis methods. In this review, we will discuss strategies to broaden the scope of reactions for DEL synthesis. These are barcoding strategies that include chemically modified DNA barcodes, solid-phase strategies, methods to solubilize the polar, polycationic DNA in non-aqueous organic solvents, and tailored catalysts for DNA-encoded chemistry.