期刊
SLAS DISCOVERY
卷 23, 期 9, 页码 951-959出版社
SAGE PUBLICATIONS INC
DOI: 10.1177/2472555218775921
关键词
native mass spectrometry; fragment-based drug discovery; noncovalent interactions
资金
- Swiss National Science Foundation [200020_140398, 200020_159929]
- Swiss National Science Foundation (SNF) [200020_140398, 200020_159929] Funding Source: Swiss National Science Foundation (SNF)
Native electrospray ionization mass spectrometry (ESI-MS) was applied to analyze the binding of compounds generated during fragment-based drug discovery (FBDD) campaigns against two functionally distinct proteins, the X-linked inhibitor of apoptosis protein (XIAP) and cyclin-dependent kinase 2 (CDK2). Compounds of different molecular weights and a wide range of binding affinities obtained from the hits to leads and lead optimization stages of FBDD campaigns were studied, and their dissociation constants (K-d) were measured by native ESI-MS. We demonstrate that native ESI-MS has the potential to be applied to the stages of an FBDD campaign downstream of primary screening for the detection and quantification of protein-ligand binding. Native ESI-MS was used to derive K-d values for compounds binding to XIAP, and the dissociation of the complex between XIAP and a peptide derived from the second mitochondria-derived activator of caspases (SMAC) protein induced by one of the test compounds was also investigated. Affinities of compounds binding to CDK2 gave K-d values in the low nanomolar to low millimolar range, and K-d values generated by MS and isothermal titration calorimetry (ITC) followed the same trend for both proteins. Practical considerations for the application of native ESI-MS are discussed in detail.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据