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Native Mass Spectrometry‐Guided Screening Identifies Hit Fragments for HOP‐HSP90 PPI Inhibition

Contemporary medicinal chemistry considers fragment‐based drug discovery (FBDD) and inhibition of protein‐protein interactions (PPI) as important means of expanding the volume of druggable chemical space. However, the ability to robustly identify valid fragments and PPI inhibitors is an enormous cha...

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Autores principales: Vaaltyn, Michaelone C., Mateos‐Jimenez, Maria, Müller, Ronel, Mackay, C. Logan, Edkins, Adrienne L., Clarke, David J., Veale, Clinton G. L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9826382/
https://www.ncbi.nlm.nih.gov/pubmed/36017658
http://dx.doi.org/10.1002/cbic.202200322
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author Vaaltyn, Michaelone C.
Mateos‐Jimenez, Maria
Müller, Ronel
Mackay, C. Logan
Edkins, Adrienne L.
Clarke, David J.
Veale, Clinton G. L.
author_facet Vaaltyn, Michaelone C.
Mateos‐Jimenez, Maria
Müller, Ronel
Mackay, C. Logan
Edkins, Adrienne L.
Clarke, David J.
Veale, Clinton G. L.
author_sort Vaaltyn, Michaelone C.
collection PubMed
description Contemporary medicinal chemistry considers fragment‐based drug discovery (FBDD) and inhibition of protein‐protein interactions (PPI) as important means of expanding the volume of druggable chemical space. However, the ability to robustly identify valid fragments and PPI inhibitors is an enormous challenge, requiring the application of sensitive biophysical methodology. Accordingly, in this study, we exploited the speed and sensitivity of nanoelectrospray (nano‐ESI) native mass spectrometry to identify a small collection of fragments which bind to the TPR2AB domain of HOP. Follow‐up biophysical assessment of a small selection of binding fragments confirmed binding to the single TPR2A domain, and that this binding translated into PPI inhibitory activity between TPR2A and the HSP90 C‐terminal domain. An in‐silico assessment of binding fragments at the PPI interfacial region, provided valuable structural insight for future fragment elaboration strategies, including the identification of losartan as a weak, albeit dose‐dependent inhibitor of the target PPI.
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spelling pubmed-98263822023-01-09 Native Mass Spectrometry‐Guided Screening Identifies Hit Fragments for HOP‐HSP90 PPI Inhibition Vaaltyn, Michaelone C. Mateos‐Jimenez, Maria Müller, Ronel Mackay, C. Logan Edkins, Adrienne L. Clarke, David J. Veale, Clinton G. L. Chembiochem Research Articles Contemporary medicinal chemistry considers fragment‐based drug discovery (FBDD) and inhibition of protein‐protein interactions (PPI) as important means of expanding the volume of druggable chemical space. However, the ability to robustly identify valid fragments and PPI inhibitors is an enormous challenge, requiring the application of sensitive biophysical methodology. Accordingly, in this study, we exploited the speed and sensitivity of nanoelectrospray (nano‐ESI) native mass spectrometry to identify a small collection of fragments which bind to the TPR2AB domain of HOP. Follow‐up biophysical assessment of a small selection of binding fragments confirmed binding to the single TPR2A domain, and that this binding translated into PPI inhibitory activity between TPR2A and the HSP90 C‐terminal domain. An in‐silico assessment of binding fragments at the PPI interfacial region, provided valuable structural insight for future fragment elaboration strategies, including the identification of losartan as a weak, albeit dose‐dependent inhibitor of the target PPI. John Wiley and Sons Inc. 2022-09-20 2022-11-04 /pmc/articles/PMC9826382/ /pubmed/36017658 http://dx.doi.org/10.1002/cbic.202200322 Text en © 2022 The Authors. ChemBioChem published by Wiley-VCH GmbH https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Vaaltyn, Michaelone C.
Mateos‐Jimenez, Maria
Müller, Ronel
Mackay, C. Logan
Edkins, Adrienne L.
Clarke, David J.
Veale, Clinton G. L.
Native Mass Spectrometry‐Guided Screening Identifies Hit Fragments for HOP‐HSP90 PPI Inhibition
title Native Mass Spectrometry‐Guided Screening Identifies Hit Fragments for HOP‐HSP90 PPI Inhibition
title_full Native Mass Spectrometry‐Guided Screening Identifies Hit Fragments for HOP‐HSP90 PPI Inhibition
title_fullStr Native Mass Spectrometry‐Guided Screening Identifies Hit Fragments for HOP‐HSP90 PPI Inhibition
title_full_unstemmed Native Mass Spectrometry‐Guided Screening Identifies Hit Fragments for HOP‐HSP90 PPI Inhibition
title_short Native Mass Spectrometry‐Guided Screening Identifies Hit Fragments for HOP‐HSP90 PPI Inhibition
title_sort native mass spectrometry‐guided screening identifies hit fragments for hop‐hsp90 ppi inhibition
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9826382/
https://www.ncbi.nlm.nih.gov/pubmed/36017658
http://dx.doi.org/10.1002/cbic.202200322
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