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Exiting the tunnel of uncertainty: crystal soak to validated hit

Lookup NU author(s): Dr Mathew Martin, Professor Martin NobleORCiD

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

Abstract

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.

Publication metadata

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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