Design concepts for DNA-Encoded Library synthesis
An approach of building block (BB) inclusivity and atom efficient library schemes deliver the quality and diversity of DNA-encoded libraries best suited for small molecule drug discovery. In this Perspective, we offer key learnings in DEL design from a decade’s worth of DEL-driven screening. It has been over 10 years since synthesis and screening of non-templated, non-bead based DNA-encoded libraries (DELs) were first reported. Since that time, numerous groups have sought to increase the scope of synthetic chemistry that can be conducted on DNA. Many successes have been reported such as metal-catalyzed C-C bond formation, photoredox chemistry, enzymatic catalysis, solid-phase immobilization, and multi-component condensations. Despite this growing body of work, there has been less attention paid to the design considerations of DELs. In this Perspective, we share our opinions around DEL library design. These opinions are based on a decade of work in applying DELs to drug hit generation. We articulate why the quality and diversity of DELs is driven primarily by the building blocks, and how this consideration influences the kinds of chemistry that are most useful for DEL synthesis. X-Chem has a long history in discovery of peptides, macrocycles and covalent inhibitors. Our libraries contain over a hundred billion compounds in these classes. This Perspective, however, focuses on conventional small molecule hit discovery. Our opinions are rooted in a conservative approach to physicochemical properties of drugs and leads. While recent work has shown that there can be promise “beyond the Rule of 5”, we believe that compact and ligand efficient starting points have the best chance of surviving the attrition of medicinal chemistry.