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

Lookup NU author(s): Cameron TaylorORCiD, Dr Grace RoperORCiD, RHIANNA Young, Professor Mike WaringORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

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.

Publication metadata

Author(s): Taylor CE, Roper G, Young R, Svensson F, Brunschweiger A, Butterworth S, Leach AG, Waring MJ

Publication type: Article

Publication status: Published

Journal: RSC Medicinal Chemistry

Year: 2025

Volume: 16

Issue: 10

Pages: 4774-4780

Print publication date: 01/10/2025

Online publication date: 29/07/2025

Acceptance date: 24/07/2025

Date deposited: 29/07/2025

ISSN (print): 2040-2503

ISSN (electronic): 2040-2511

Publisher: Royal Society of Chemistry

URL: https://doi.org/10.1039/D5MD00350D

DOI: 10.1039/D5MD00350D

Data Access Statement: Full experimental details and data supporting this article are available in the supplementary information.

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