A next-generation label-free MALDI mass spectrometry based high-throughput screening solution taking advantage of timsTOF technology

MALDI mass spectrometry (MALDI-MS) has evolved into an established, highly capable label-free HTS readout method accelerating drug discovery. MALDI-MS enables fast reading rates of up to multiple wells per second and has proven itself to feature an outstanding level of robustness. As a result of this, MALDI-MS has been successfully applied to full-deck screening of primary compound libraries comprising a million or even more compounds at unparalleled speed.

We introduce here timsTOF MALDI PharmaPulse (timsTOF MPP), a next-generation MALDI-MS based solution for label-free HTS taking advantage of new and innovative timsTOF technology. timsTOF relies on ultrahigh-resolution time of flight mass spectrometry (UHR-TOF) in combination with trapped ion mobility spectrometry (TIMS) as an upfront ultrafast dimension of separation orthogonal to MS.

The new HTS platform offers the following unique key features:

1) For the first time ever, ultrafast MALDI based HTS readout (up to 3 wells / sec) is available in combination with high-resolution mass spectrometry.
2) Robust and reliable quantitative feature extraction from high-resolution MS data enhances the confidence level of HTS results for a wide spectrum of target compounds ranging from small molecules to larger sized peptides.
3) Assay specificity is improved significantly by engaging advanced timsTOF operation modes (e.g. MS/MS, TIMS) resulting in lowered FDR and expanded quantitation range.
4) TIMS provides an additional dimension of separation in the gas phase being significantly faster than LC or SPE (≤ 1s per separation cycle, typically). TIMS is capable of separating isobars and isomers and allows, therefore, quantitation of target compounds indistinguishable by mass spectrometry alone.
5) Beyond quantitative HTS assays, timsTOF MPP enables high-confidence near real-time verification of chemical synthesis products based on multiple physical properties, i.e. accurate molecular mass, isotope pattern, collisional cross-section (CCS) and, on demand, MS/MS fragmentation, thus reducing feedback time and chemical costs in high-throughput experimentation (HTE) chemistry.
6) As part of the timsTOF MPP solution, tailored application software is available to support seamless campaign setup and execution in various HTS workflows, system integration in a fully automatized HTS environment via an integrated automation interface and data transfer to external software for further downstream analysis.