Re‐Imagining Drug Discovery using Mass Spectrometry

Abstract

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.

Ultrafast C–C and C–N bond formation reactions in water microdroplets facilitated by the spontaneous generation of carbocations

“…In this circumstance, the outer layer is rich in protons that can act as a superacid, forming stable diarylcarbenium ions. 54,55 Other studies 56 opine that aromatic compounds in microdroplets preferentially inhabit the air-water interface, positioning the aromatic ring towards the air side while the -OH group remains embedded in water. Such a high electric eld has the potential to break the C-O bond, thus leading to the production of the diarylcarbenium ions at the interface of the microdroplet.…”

High‐Throughput Diversification of Complex Bioactive Molecules by Accelerated Synthesis in Microdroplets

“…It is noteworthy that the HT DESI methodology can be extended to bioassays [9f, g] so completing the drug discovery triad of reaction screening, synthesis, and bioactivity measurement. [30]…”

Desorption Electrospray Ionization Mass Spectrometry: 20 Years

“…Through these studies, the scaled-up synthesis of anticancer drugs has been optimized, 71 and recently the late-stage functionalization of complex bioactive compounds such as opioids has been demonstrated. 67,73 Note that, after the initial screening, samples can be re-examined, in particular by MS/ MS, for online structural confirmation of reaction products. 69,72,73 The tolerance of DESI to typical bioassay matrix components (i.e., high concentrations of buffers, nonvolatile salts such as phosphates, and detergents), which are commonly inimical to MS analysis, allowed for the expansion of the system capabilities into biological space.…”

“…In practice, access to these accelerating conditions is favored by longer droplet flight times; therefore, short spray distances can be chosen to create “analytical” conditions and long distances for “synthetic” conditions. Also note that DESI droplets containing the products of accelerated reactions can be sampled by a mass spectrometer, or alternatively they can simply be intercepted in order to collect nanograms of reaction products for facile product characterization by other means or for assessment of their biological activities …”