Native mass spectrometry guided screening identifies hit fragments for HOP-HSP90 PPI inhibition

03 November 2021, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Contemporary medicinal chemistry considers fragment-based drug discovery (FBDD) and inhibition of Protein-Protein Interactions (PPI), as important means of expanding 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 nano-ESI native mass spectrometry to identify a small collection of fragments, which bind to the TPR2AB domain of HOP. Further biological assessment of a small selection of binding fragments showed that this binding translated into PPI inhibitory activity between the TPR2A domain of HOP 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.


Fragment Based Drug Design
Native Mass Spectrometry
Protein-Protein Interaction Inhibition
Heat Shock Protein 90
HSP70-HSP90 Organising Protein


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