Development of a target identification approach using native mass spectrometry
Abstract A key step in the development of new pharmaceutical drugs is the identification of the molecular target and distinguishing this from all other gene products that respond indirectly to the drug. Target identification remains a crucial process and a current bottleneck for advancing hits throu...
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2021-01-01
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Series: | Scientific Reports |
Online Access: | https://doi.org/10.1038/s41598-021-81859-4 |
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doaj-79735f1a181546f9a030b3da081e8bf62021-01-31T16:25:21ZengNature Publishing GroupScientific Reports2045-23222021-01-0111111210.1038/s41598-021-81859-4Development of a target identification approach using native mass spectrometryMiaomiao Liu0Wesley C. Van Voorhis1Ronald J. Quinn2Griffith Institute for Drug Discovery, Griffith UniversityDepartment of Medicine, Center for Emerging and Re-Emerging Infectious Diseases, University of WashingtonGriffith Institute for Drug Discovery, Griffith UniversityAbstract A key step in the development of new pharmaceutical drugs is the identification of the molecular target and distinguishing this from all other gene products that respond indirectly to the drug. Target identification remains a crucial process and a current bottleneck for advancing hits through the discovery pipeline. Here we report a method, that takes advantage of the specific detection of protein–ligand complexes by native mass spectrometry (MS) to probe the protein partner of a ligand in an untargeted method. The key advantage is that it uses unmodified small molecules for binding and, thereby, it does not require labelled ligands and is not limited by the chemistry required to tag the molecule. We demonstrate the use of native MS to identify known ligand–protein interactions in a protein mixture under various experimental conditions. A protein–ligand complex was successfully detected between parthenolide and thioredoxin (PfTrx) in a five-protein mixture, as well as when parthenolide was mixed in a bacterial cell lysate spiked with PfTrx. We provide preliminary data that native MS could be used to identify binding targets for any small molecule.https://doi.org/10.1038/s41598-021-81859-4 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Miaomiao Liu Wesley C. Van Voorhis Ronald J. Quinn |
spellingShingle |
Miaomiao Liu Wesley C. Van Voorhis Ronald J. Quinn Development of a target identification approach using native mass spectrometry Scientific Reports |
author_facet |
Miaomiao Liu Wesley C. Van Voorhis Ronald J. Quinn |
author_sort |
Miaomiao Liu |
title |
Development of a target identification approach using native mass spectrometry |
title_short |
Development of a target identification approach using native mass spectrometry |
title_full |
Development of a target identification approach using native mass spectrometry |
title_fullStr |
Development of a target identification approach using native mass spectrometry |
title_full_unstemmed |
Development of a target identification approach using native mass spectrometry |
title_sort |
development of a target identification approach using native mass spectrometry |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2021-01-01 |
description |
Abstract A key step in the development of new pharmaceutical drugs is the identification of the molecular target and distinguishing this from all other gene products that respond indirectly to the drug. Target identification remains a crucial process and a current bottleneck for advancing hits through the discovery pipeline. Here we report a method, that takes advantage of the specific detection of protein–ligand complexes by native mass spectrometry (MS) to probe the protein partner of a ligand in an untargeted method. The key advantage is that it uses unmodified small molecules for binding and, thereby, it does not require labelled ligands and is not limited by the chemistry required to tag the molecule. We demonstrate the use of native MS to identify known ligand–protein interactions in a protein mixture under various experimental conditions. A protein–ligand complex was successfully detected between parthenolide and thioredoxin (PfTrx) in a five-protein mixture, as well as when parthenolide was mixed in a bacterial cell lysate spiked with PfTrx. We provide preliminary data that native MS could be used to identify binding targets for any small molecule. |
url |
https://doi.org/10.1038/s41598-021-81859-4 |
work_keys_str_mv |
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