2 research outputs found
Native Mass Spectrometry-Guided Screening Identifies Hit Fragments for HOP-HSP90 PPI Inhibition
Contemporary medicinal chemistry considers fragmentâbased drug discovery (FBDD) and inhibition of proteinâprotein 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 (nanoâESI) native mass spectrometry to identify a small collection of fragments which bind to the TPR2AB domain of HOP. Followâup 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 Câterminal domain. An inâsilico 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 doseâdependent inhibitor of the target PPI