TY - JOUR
T1 - Native Mass Spectrometry-Guided Screening Identifies Hit Fragments for HOP-HSP90 PPI Inhibition
AU - Vaaltyn, Michaelone C.
AU - Mateos-Jimenez, Maria
AU - Müller, Ronel
AU - Mackay, C. Logan
AU - Edkins, Adrienne L.
AU - Clarke, David J.
AU - Veale, Clinton G.L.
N1 - Funding Information:
The authors would like to acknowledge support from the Royal Society‐Newton Fund (Grant No. NI160018), the BBSRC (Grant No. BB/R013993/1), Rhodes University, the National Research Foundation of South Africa (NRF, Grant Nos. 105829, 116305, 127224, 129262), the South African Research Chairs Initiative of the Department of Science and Innovation (DSI) and NRF (Grant No. 98566), and Future Leaders – African Independent Research (FLAIR), a partnership between the African Academy of Sciences and the Royal Society that is funded by the UK Government as part of the Global Challenge Research Fund (GCRF). RM and MCV gratefully acknowledge postdoctoral and postgraduate funding support from the NRF. We thank Dr Faye Cruickshank of the SIRCAMS mass spectrometry facility at the School of Chemistry, University of Edinburgh for technical support, Ms Kim Germiquet for ‘sartan’ samples and the Centre for High Performance Computing (CHPC) for access to Schrodinger's modelling suite.
Publisher Copyright:
© 2022 The Authors. ChemBioChem published by Wiley-VCH GmbH.
PY - 2022/8/26
Y1 - 2022/8/26
N2 - 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.
AB - 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.
KW - fragment-based drug discovery
KW - heat shock protein 90
KW - HSP70-HSP90 organizing protein
KW - native mass spectrometry
KW - PPI inhibitors
U2 - 10.1002/cbic.202200322
DO - 10.1002/cbic.202200322
M3 - Article
C2 - 36017658
AN - SCOPUS:85138290957
VL - 23
JO - ChemBioChem
JF - ChemBioChem
SN - 1439-4227
IS - 21
M1 - e202200322
ER -