JEDEL: Zero-Shot DNA-Encoded Library Design for Early-Stage Drug Discovery

JEDEL is a novel framework for generating synthesis-ready DNA-encoded libraries (DELs) from three-dimensional pharmacophore representations, allowing for the design of targeted libraries with potentially millions of molecules. It uniquely maps pharmacophore interaction patterns to practical synthesis instructions using purchasable building blocks and validated reactions, ensuring outputs are experimentally realizable. Evaluated across 18 protein targets, JEDEL demonstrates superior performance in predicted binding affinity and sample efficiency compared to traditional random and diversity-based approaches, marking a significant advancement in drug discovery methodologies.