Early-Stage Drug Discovery in an Automated Ultrahigh-Throughput Ambient Mass Spectrometry Platform

The early drug discovery workflow relies heavily on high-throughput (HT) experimentation, both in terms of organic synthesis as well as analysis of complex biosamples. The identification of new biological targets through large-scale biospecimen studies, the generation of large sets of drug candidates and their rapid bioactivity screening, as well as the confirmation of hits followed by lead optimization, all rely on HT strategies typically spread out across diverse technologies in specialized facilities. The efficiency of this workflow could then benefit from consolidating all these activities on a single closed-loop platform. Mass spectrometry (MS), due to its inherent speed, is an attractive technique to achieve this, however its potential is rarely fully utilized due to the widespread use of sample purification approaches prior to MS.
Here we describe an automated system that achieves the consolidation of the early drug discovery pipeline by leveraging the advantages of desorption electrospray ionization (DESI), an ambient ionization technique that allows for the rapid and direct analysis of complex samples, both in qualitative and quantitative manner, without any need for workup. This system results from the combination of custom and commercial software, robotics, and analytical instrumentation, and it can achieve throughputs of up to 3 Hz using high-density arrays (up to 6,144 samples) and (sub)ng samples. More significantly, the inherent reaction acceleration phenomenon that occurs in microdroplets, such as those generated with DESI, allows reaction times to be reduced to just milliseconds, effectively providing an on-the-fly synthetic method that can be coupled with in operando MS analysis or small-scale product collection for bioactivity assessment. Examples of all these capabilities will be provided and framed within the context of direct-to-biology drug discovery using a new-generation ultra-HT-DESI-MS system developed within the NCATS ASPIRE initiative.