Lookup NU author(s): Daniel Wood,
Daniel Lopez Fernandez,
Dr Mathew Martin,
Dr Celine Cano,
Professor Jane Endicott,
Dr Ian Hardcastle,
Professor Martin Noble,
Professor Mike Waring
This is the authors' accepted manuscript of an article that has been published in its final definitive form by American Chemical Society, 2019.
For re-use rights please refer to the publisher's terms and conditions.
Identifying ligand binding sites on proteins is a critical step in target-based drug discovery. Current approaches to this require resource intensive screening of large libraries of lead-like or fragment molecules. Here we describe an efficient and effective experimental approach to mapping interaction sites using a set of halogenated compounds expressing paired hydrogen-bonding motifs, termed FragLites. The FragLites identify productive drug-like interactions, which are identified sensitively and unambiguously by X-ray crystallography, exploiting the anomalous scattering of the halogen substituent. This mapping of protein interaction surfaces provides an assessment of druggability and can identify efficient start points for the de novo design of hit molecules incorporating the interacting motifs. The approach is illustrated by mapping cyclin-dependent kinase 2, which successfully identifies orthosteric and allosteric sites. The hits were rapidly elaborated to develop efficient lead-like molecules. Hence, the approach provides a new method of identifying ligand sites, assessing tractability and discovering new leads.
Author(s): Wood D, Lopez-Fernandez JD, Knight LE, Al-Khawaldeh I, Gai C, Lin S, Martin MP, Miller DC, Cano C, Endicott JA, Hardcastle IR, Noble MEM, Waring MJ
Publication type: Article
Publication status: Published
Journal: Journal of Medicinal Chemistry
Print publication date: 11/04/2019
Online publication date: 12/03/2019
Acceptance date: 11/03/2019
Date deposited: 18/03/2019
ISSN (print): 0022-2623
ISSN (electronic): 1520-4804
Publisher: American Chemical Society
PubMed id: 30860382
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