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Exiting the tunnel of uncertainty: crystal soak to validated hit
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 hi...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
International Union of Crystallography
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9629488/ https://www.ncbi.nlm.nih.gov/pubmed/36322414 http://dx.doi.org/10.1107/S2059798322009986 |
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author | Martin, Mathew P. Noble, Martin E. M. |
author_facet | Martin, Mathew P. Noble, Martin E. M. |
author_sort | Martin, Mathew P. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9629488 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | International Union of Crystallography |
record_format | MEDLINE/PubMed |
spelling | pubmed-96294882022-11-14 Exiting the tunnel of uncertainty: crystal soak to validated hit Martin, Mathew P. Noble, Martin E. M. Acta Crystallogr D Struct Biol Ccp4 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. International Union of Crystallography 2022-10-27 /pmc/articles/PMC9629488/ /pubmed/36322414 http://dx.doi.org/10.1107/S2059798322009986 Text en © Martin and Noble 2022 https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited. |
spellingShingle | Ccp4 Martin, Mathew P. Noble, Martin E. M. Exiting the tunnel of uncertainty: crystal soak to validated hit |
title | Exiting the tunnel of uncertainty: crystal soak to validated hit |
title_full | Exiting the tunnel of uncertainty: crystal soak to validated hit |
title_fullStr | Exiting the tunnel of uncertainty: crystal soak to validated hit |
title_full_unstemmed | Exiting the tunnel of uncertainty: crystal soak to validated hit |
title_short | Exiting the tunnel of uncertainty: crystal soak to validated hit |
title_sort | exiting the tunnel of uncertainty: crystal soak to validated hit |
topic | Ccp4 |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9629488/ https://www.ncbi.nlm.nih.gov/pubmed/36322414 http://dx.doi.org/10.1107/S2059798322009986 |
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