Re-imagining Drug Discovery using Automated Ambient Mass Spectrometry

Abstract

The early drug discovery workflow relies heavily on high-throughput 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 in vitro and cell-based confirmation of hits followed by lead optimization, all rely on high-throughput strategies which are typically spread out across diverse technologies in specialized facilities. The efficiency of this workflow could benefit from the consolidation of these activities in a single closed-loop platform. Mass spectrometry (MS) is an attractive technique to achieve such consolidation due to the inherent speed of mass analysis, however this advantage is rarely fully utilized due to the widespread use of sample purification approaches (e.g. chromatography) 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 its capable of achieving throughputs better than 1 Hz using high-density arrays (up to 6,144 samples per array) and 50-nL samples (<5 ng analyte). This platform, which is available as a facility resource under the Bindley Bioscience Center at Purdue University, has been extensively utilized for the screening of organic reactions for identification of optimal synthesis conditions and the selective late-stage functionalization of complex molecules, as well as label-free quantitative biological assays using purified targets (e.g. enzymes, receptors), cell cultures, microorganisms, or tissue biopsies, all with no sample cleanup. Examples of all these capabilities will be provided and framed within the overall context of drug discovery.