Native Mass Spectrometry‐Guided Screening Identifies Hit Fragments for HOP‐HSP90 PPI Inhibition. (20th September 2022)

• Record Type: Journal Article
• Authors: Vaaltyn, Michaelone C.; Mateos‐Jimenez, Maria; Müller, Ronel; Mackay, C. Logan; Edkins, Adrienne L.; Clarke, David J.; Veale, Clinton G. L.
• Is Part Of: Chembiochem. Volume 23:Number 21(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-09-20
• Subjects: fragment-based drug discovery -- native mass spectrometry -- PPI inhibitors -- heat shock protein 90 -- HSP70-HSP90 organizing protein; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.202200322
• Languages: English
• ISSNs: 1439-4227

Abstract

Abstract: 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. Abstract : We sought to demonstrate the combined utility of native mass spectrometry (MS), and fragment‐based drug discovery as a viable means for identifying protein‐protein interaction (PPI) inhibitors. Here we identified a small cohort of molecular fragments, who's binding to the TPR2AB region of our target, HOP, translated into inhibition of the PPI between the TPR2A domain of HOP and the HSP90 C ‐terminus.