Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 55, Issue 2, Pages 837-851Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm201347k
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Funding
- UCB Pharma
- Slough, U.K.
- BBSRC [BB/E528895/1]
- BBSRC [BB/E528895/1] Funding Source: UKRI
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Identifying protein-ligand binding interactions is a key step during early-stage drug discovery. Existing screening techniques are often associated with drawbacks such as low throughput, high sample consumption, and dynamic range limitations. The increasing use of fragment-based drug discovery (FBDD) demands that these techniques also detect very weak interactions (mM K-D values). This paper presents the development and validation of a fully automated screen by mass spectrometry, capable of detecting fragment binding into the millimolar K-D range. Low sample consumption, high throughput, and wide dynamic range make this a highly attractive, orthogonal approach. The method was applied to screen 157 compounds in 6 h against the anti-apoptotic protein target Bcl-x(L). Mass spectrometry results were validated using STD-NMR, HSQC-NMR, and ITC experiments. Agreement between techniques suggests that mass spectrometry offers a powerful, complementary approach for screening.
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