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Mapping ligand interactions of bromodomains BRD4 and ATAD2 with FragLites and PepLites ─ Halogenated probes of druglike and peptide-like molecular interactions

Lookup NU author(s): Gemma Davison, Dr Mathew Martin, Dr Shannon TurbervilleORCiD, Selma Dormen, Dr Richard Heath, Amy Heptinstall, Dr Marie Lawson, Duncan Miller, Yi Min Ng Ng, Dr James Sanderson, Dr Ian Hope, Daniel Wood, Dr Celine CanoORCiD, Professor Jane Endicott, Dr Ian HardcastleORCiD, Professor Martin NobleORCiD, Professor Mike Waring



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


The development of ligands for biological targets is critically dependent on the identification of sites on proteins that bind molecules with high affinity. A set of compounds, called FragLites, can identify such sites, along with the interactions required to gain affinity, by X-ray crystallography. We demonstrate the utility of FragLites in mapping the binding sites of bromodomain proteins BRD4 and ATAD2 and demonstrate that FragLite mapping is comparable to a full fragment screen in identifying ligand binding sites and key interactions. We extend the FragLite set with analogous compounds derived from amino acids (termed PepLites) that mimic the interactions of peptides. The output of the FragLite maps is shown to enable the development of ligands with leadlike potency. This work establishes the use of FragLite and PepLite screening at an early stage in ligand discovery allowing the rapid assessment of tractability of protein targets and informing downstream hit-finding.

Publication metadata

Author(s): Davison G, Martin MP, Turberville S, Dormen S, Heath R, Heptinstall AB, Lawson M, Miller DC, Ng YM, Sanderson JN, Hope I, Wood DJ, Cano C, Endicott JA, Hardcastle IR, Noble MEM, Waring MJ

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 2022

Volume: 65

Issue: 22

Pages: 15416-15432

Print publication date: 24/11/2022

Online publication date: 11/11/2022

Acceptance date: 11/11/2022

Date deposited: 07/12/2022

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

Publisher: American Chemical Society


DOI: 10.1021/acs.jmedchem.2c01357


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Funder referenceFunder name
C2115/A21421Cancer Research UK CRUK (closed comp)
C57659/A27310Cancer Research UK CRUK (open competition)
MR/N009738/1Medical Research Council (MRC)
Newcastle University