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Lookup NU author(s): Dr Mathew Martin, Professor Martin NobleORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Open access. Crystallographic fragment screens provide an efficient and effective way to identify small-molecule ligands of a crystallized protein. Due to their low molecular weight, such hits tend to have low, often unquantifiable, affinity for their target, complicating the twin challenges of validating the hits as authentic solution-phase ligands of the target and identifying the `best' hit(s) for further elaboration. In this article, approaches that address these challenges are assessed. Using retrospective analysis of a recent ATAD2 hit-identification campaign, alongside other examples of successful fragment-screening campaigns, it is suggested that hit validation and prioritization are best achieved by a `triangulation' approach in which the results of multiple available biochemical and biophysical techniques are correlated to develop qualitative structure-activity relationships (SARs). Such qualitative SARs may indeed be the only means by which to navigate a project through the tunnel of uncertainty that prevails before on-scale biophysical, biochemical and/or biological measurements become possible.
Author(s): Martin MP, Noble MEM
Publication type: Article
Publication status: Published
Journal: Acta Crystallographica. Section D, Structural Biology
Year: 2022
Volume: D78
Issue: 11
Pages: 1294-1302
Online publication date: 01/11/2022
Acceptance date: 12/10/2022
Date deposited: 28/11/2022
ISSN (electronic): 2059-7983
Publisher: Wiley-Blackwell Publishing, Inc.
URL: https://doi.org/10.1107/S2059798322009986
DOI: 10.1107/S2059798322009986
PubMed id: 36322414
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