Diversity-oriented synthesis encoded by deoxyoligonucleotides

AbstractDiversity-oriented synthesis (DOS) is a powerful strategy to prepare molecules with underrepresented features in commercial screening collections, a direct result of which has been to elucidate novel biological mechanisms of action. Running in parallel to the development of DOS over the past few decades, DNA-encoded libraries (DELs) have emerged as an effective and efficient screening strategy to identify protein binders. Yet, despite recent advancements in this field most DEL syntheses are limited by the presence of sensitive DNA-based constructs. Here we describe the design, synthesis and validation experiments performed for a 3.7 million-member DEL using diverse skeleton architectures derived from DOS to achieve structural diversity beyond that afforded by varying appendages alone. We will make this encoded collection available to the academic scientific community to increase access to novel structural features and accelerate early-phase drug discovery.