The Biomedical Biotechnology Research Unit (BioBRU) Department of Biochemistry and Microbiology Department, Rhodes University, Makhanda, 6139, South Africa.
EaStCHEM School of Chemistry, Joseph Black Building, David Brewster Road, Edinburgh, EH93FJ, UK.
Chembiochem. 2022 Nov 4;23(21):e202200322. doi: 10.1002/cbic.202200322. Epub 2022 Sep 20.
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.
当代药物化学将基于片段的药物发现 (FBDD) 和蛋白质-蛋白质相互作用 (PPI) 的抑制作用视为扩展可成药化学空间的重要手段。然而，稳健地识别有效片段和 PPI 抑制剂的能力是一个巨大的挑战，需要应用敏感的生物物理方法。因此，在这项研究中，我们利用纳喷雾 (nano-ESI) 天然质谱的速度和灵敏度来鉴定一小部分与 HOP 的 TPR2AB 结构域结合的片段。对一小部分结合片段的后续生物物理评估证实了与单个 TPR2A 结构域的结合，并且这种结合转化为 TPR2A 和 HSP90 C 末端结构域之间的 PPI 抑制活性。在 PPI 界面区域对结合片段进行的计算评估为未来的片段设计策略提供了有价值的结构见解，包括鉴定洛沙坦作为靶 PPI 的弱但剂量依赖性抑制剂。
