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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.
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
URL: https://doi.org/10.1021/acs.jmedchem.2c01357
DOI: 10.1021/acs.jmedchem.2c01357
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