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

Michaelone C. Vaaltyn, Maria Mateos-Jimenez, Ronel Müller, C. Logan Mackay, Adrienne L. Edkins, David J. Clarke, Clinton G.L. Veale*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
Article numbere202200322
Issue number21
Early online date26 Aug 2022
Publication statusE-pub ahead of print - 26 Aug 2022

Keywords / Materials (for Non-textual outputs)

  • fragment-based drug discovery
  • heat shock protein 90
  • HSP70-HSP90 organizing protein
  • native mass spectrometry
  • PPI inhibitors


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