Selection Strategies in DNA-Encoded Libraries

Abstract

DNA-encoded chemical library (DEL) has emerged as a versatile and innovative technology platform for ligand discovery in chemical biology research and early-stage drug discovery. The rapid development of DEL-compatible reactions has further fueled its applications over the last decade. To date, DELs have been widely adopted by the pharmaceutical industry and are also gaining popularity in academic research. However, a relatively underexplored component of DELs is the selection methodology. DEL selection has been generally considered a massive binding assay, which has been dominated by the so-called bind-wash-elute procedure against immobilized protein targets. Indeed, such a “classical” selection method has seen great success in the selection campaigns against numerous drug targets. Recently, novel DEL selection modalities have emerged, which have not only widened the target scope of DELs to the complex milieu of biological systems but also enabled functional DEL selections beyond identifying physical binders. This chapter furnishes an overview of the current DEL selection methods and concludes with a perspective for future development, aiming to provide a succinct guidance for practitioners who intend to embrace the DEL technology.