期刊
CHEMBIOCHEM
卷 23, 期 21, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.202200322
关键词
fragment-based drug discovery; native mass spectrometry; PPI inhibitors; heat shock protein 90; HSP70-HSP90 organizing protein
资金
- Royal Society-Newton Fund [NI160018]
- BBSRC [BB/R013993/1]
- Rhodes University
- National Research Foundation of South Africa (NRF) [105829, 116305, 127224, 129262]
- South African Research Chairs Initiative of the Department of Science and Innovation (DSI)
- NRF [98566]
- African Academy of Sciences - UK Government as part of the Global Challenge Research Fund (GCRF)
- Royal Society - UK Government as part of the Global Challenge Research Fund (GCRF)
- NRF
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. This study utilized the speed and sensitivity of nanoelectrospray (nano-ESI) native mass spectrometry to identify fragments that bind to the TPR2AB domain of HOP. The fragments were validated through biophysical assessment, demonstrating binding and inhibitory activity against the TPR2A domain and the HSP90 C-terminal domain.
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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