Re‐Imagining Drug Discovery using Mass Spectrometry

• Published in: Israel journal of chemistry Vol. 63; no. 7-8
• Main Authors: Cooks, R. Graham, Feng, Yunfei, Huang, Kai‐Hung, Morato, Nicolás M., Qiu, Lingqi
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.08.2023
• Subjects: automation; bioanalytical; Buffers (chemistry); Desorption electrospray ionization; Droplets; high-throughput screening; Ionization; Ions; late-stage functionalization; Mass spectrometry; Scientific imaging; Synthesis; tandem mass spectrometry; automation; tandem mass spectrometry; bioanalytical; late-stage functionalization; Desorption electrospray ionization; high-throughput screening
• ISSN: 0021-2148; 1869-5868
• DOI: 10.1002/ijch.202300034

It is argued that each of the three key steps in drug discovery, (i) reaction screening to find successful routes to desired drug candidates, (ii) scale up of the synthesis to produce amounts adequate for testing, and (iii) bioactivity assessment of the candidate compounds, can all be performed using mass spectrometry (MS) in a sequential fashion. The particular ionization method of choice, desorption electrospray ionization (DESI), is both an analytical technique and a procedure for small‐scale synthesis. It is also highly compatible with automation, providing for high throughput in both synthesis and analysis. Moreover, because accelerated reactions take place in the secondary DESI microdroplets generated from individual reaction mixtures, this allows either online analysis by MS or collection of the synthetic products by droplet deposition. DESI also has the unique advantage, amongst spray‐based MS ionization methods, that complex buffered biological solutions can be analyzed directly, without concern for capillary blockage. Here, all these capabilities are illustrated, the unique chemistry at droplet interfaces is presented, and the possible future implementation of DESI‐MS based drug discovery is discussed.