Herein we describe a native mass spectromery protein-peptide model as a competent surrogate for the HOP–HSP90 Protein-Protein Interaction (PPI), application of which led to the qualititive identification of two new...
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.
This communication discusses for the first time, the use of mass spectrometry as a platform for screening for PPI inhibitors, without protein tethering or labeling. Furthermore, in the context of cancer drug discovery, this study demonstrates the ligandability and therefore the potential druggability of HOP, whose PPI with HSP90 has been routinely discussed as a difficult to drug target of substantial potential.
This communication discusses for the first time, the use of mass spectrometry as a platform for screening for PPI inhibitors, without protein tethering or labeling. Furthermore, in the context of cancer drug discovery, this study demonstrates the ligandability and therefore the potential druggability of HOP, whose PPI with HSP90 has been routinely discussed as a difficult to drug target of substantial potential.
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.
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