20 February / March 2021
The Only Thing Faster Than Ultra-Fast Is Instantaneous
by Neil Walsh, Senior Manager for Pharma, Global Strategic Marketing, SCIEX [Framingham, MA, USA]
Abstract
True high-throughput screening of candidate compounds during drug discovery has been hindered by the limitations of traditional liquid chromatography (LC), such as method development, sample preparation and sample throughput that prevents it from being more widely applicable. Acoustic Ejection Mass Spectrometry (AEMS) leveraging Acoustic Droplet Ejection (ADE) technology combined with an Open Port Interface (OPI) allows sample analyses at speeds up to 50 times faster than conventional LC-mass spectrometry.
Need to Speed Up High- Throughput Drug Discovery
Drug discovery today involves evaluation of massive compound libraries of thousands, or even millions, of potential drug candidates. High-throughput screening (HTS) to assess the pharmacokinetic (PK) properties of molecules is essential for lead candidate selection in a practical timeframe. Analyses are typically performed using plate reading technology because of the speed, but have inherent development costs and specificity issues. Liquid chromatography (LC), or high-performance LC (HPLC), for separation and mass spectrometry (MS) for detection have the specificity and information rich data, but currently lack the speed for wider applicability.
When plate reading technology is used, the output is typically based on a reaction of the compound that generates an absorption or emission. This is a simple end point, but lacks specificity and can become complicated to develop and troubleshoot. Often, secondary screens are needed to evaluate false positives. LC-MS/ MS methodologies currently have high specificity but low throughput due to sample preparation and separation workflows, which are rate limiting bottlenecks for HTS. There is a need for simple ultra-high throughput sampling that directly measures product and substrate, enables HTS screening with complex biology and delivers unequivocal endpoints, to reduce ambiguity and enable better decision-making on progression of a therapeutic along the development pipeline.
Simplification Through LC Elimination
Acoustic Ejection Mass Spectrometry (AEMS) combines both Acoustic Droplet Ejection (ADE) technology and Open Port Interface (OPI) technology [1] to enable direct contactless sampling into an electrospray ionisation mass spectrometer (ESI-MS). It has the potential to eliminate the limitations associated with LC-based sample introduction. At the same time, the technology provides access to ultra-fast sampling at the same speeds as the incumbent plate reader technology in HTS, but with the specificity and information-rich data of MS.
With AEMS, nanolitre-sized sample droplets are ejected via the application of
sound waves focused at the bottom of the sample well. The ejected samples from the microwell plate are captured into the vortex of the OPI. The sample is then diluted with carrier solvent and delivered directly to the electrospray source, ionised via conventional electrospray and detected by the mass spectrometer (Figure 1). No injection needles or loops are required. Sample introduction into the MS is achieved through a contactless interaction of the ADE with the OPI, virtually eliminating sample-to-sample carryover, even when moving between concentration extremes. Matrix suppression effects are also essentially eliminated due to dilution effects that occur within the OPI, allowing for clean and sensitive analyses for most molecules in drug discovery.
Figure 1. Acoustic Ejection Mass Spectrometry (AEMS) setup for contactless electrospray ionisation mass spectrometry (ESI-MS).
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