Design and synthesis of a chemically diverse, lead-like DNA-encoded library from sequential amide coupling

Abstract

DNA-encoded libraries (DELs) are established as an effective screening strategy to identify protein ligands and offer a cost-effective means of screening large numbers of compounds. However, the synthesis and utilisation of DELs is implemented by relatively few laboratories. Here, we describe the design and synthesis of a medium-sized DEL through simple amide coupling procedures. We provide details of chemistry and enzymatic steps and demonstrate their effectiveness by synthesising 300k and 3M-member DELs. We demonstrate their integrity through screening against carbonic anhydrase IX and show their chemical diversity through in silico comparison with an established high-throughput screening library. The DELs described can be used as a resource to accelerate hit identification for early-phase drug discovery and are available to the academic community for screening.

Supplementary files

Article information

Article type
Research Article
Submitted
22 Apr 2025
Accepted
24 Jul 2025
First published
29 Jul 2025
This article is Open Access
Creative Commons BY license

RSC Med. Chem., 2025, Accepted Manuscript

Design and synthesis of a chemically diverse, lead-like DNA-encoded library from sequential amide coupling

C. Taylor, G. Roper, R. Young, F. Svensson, A. Brunschweiger, S. Butterworth, A. Leach and M. J. Waring, RSC Med. Chem., 2025, Accepted Manuscript , DOI: 10.1039/D5MD00350D

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