Small-molecule drug discovery can be viewed as a challenging multidimensional problem in which various characteristics of compounds - including efficacy, pharmacokinetics and safety - need to be optimized in parallel to provide drug candidates. Recent advances in areas such as microfluidics-assisted chemical synthesis and biological testing, as well as artificial intelligence systems that improve a design hypothesis through feedback analysis, are now providing a basis for the introduction of greater automation into aspects of this process. This could potentially accelerate time frames for compound discovery and optimization and enable more effective searches of chemical space. However, such approaches also raise considerable conceptual, technical and organizational challenges, as well as scepticism about the current hype around them. This article aims to identify the approaches and technologies that could be implemented robustly by medicinal chemists in the near future and to critically analyse the opportunities and challenges for their more widespread application.

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Automating drug discovery

Dalton T. Snyder,† Christopher J. Pulliam,† Zheng Ouyang,‡ and R. Graham Cooks*,† †Department of Chemistry and Center for Analytical Instrumentation Development, Purdue University, West Lafayette, Indiana 47907, United States ‡Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana 47907, United States ■ CONTENTS Ambient Ionization and Sampling 2 Vacuum Systems 4 Analyzers and Configurations 6 MEMS and Other Alternative Fabrication Methods 8 Simulations 9 Electronics and Data Systems 12 Portable Systems 19 Mesoscale Systems 20 Planetary and Space Science Systems 21 Practical Applications 22 Expectations 23 Author Information 23 Corresponding Author 23 Notes 23 Biographies 23 Acknowledgments 24 References 24

Miniature and Fieldable Mass Spectrometers: Recent Advances.

The striking finding that reaction acceleration occurs in confined-volume solutions sets up an apparent conundrum: Microdroplets formed by spray ionization can be used to monitor the course of bulk-phase reactions and also to accelerate reactions between the reagents in such a reaction. This Minireview introduces droplet and thin-film acceleration phenomena and summarizes recent methods applied to study accelerated reactions in confined-volume, high-surface-area solutions. Conditions that dictate either simple monitoring or acceleration are reconciled in the occurrence of discontinuous and complete desolvation as the endpoint of droplet evolution. The contrasting features of microdroplet and bulk-solution reactions are described together with possible mechanisms that drive reaction acceleration in microdroplets. Current applications of droplet microreactors are noted as is reaction acceleration in confined volumes and possible future scale-up.

Organic Reactions in Microdroplets: Reaction Acceleration Revealed by Mass Spectrometry.

The early 2000s brought a new age in the field of mass spectrometry (MS) with the introduction of ambient ionization MS techniques. As defined by one of its early visionaries, Prof. R. Graham Cooks, ambient ionization refers to \"the ionization of unprocessed or minimally modified samples in their native environment, and it typically refers to the ionization of condensed phase samples in air.\" Since its inception in 2004, many researchers and laboratories have contributed with approaches for sampling and ionization at atmospheric conditions, greatly decreasing experimental complexity and time required for mass spectrometry analyses. In the last 15 years, innovations in the field of ambient ionization MS have grown expansively, pushing these technologies far past their point of conception and integrating them into the broader scientific community in creative and stimulating ways.

Ambient ionization Mass Spectrometry: Recent Developments and Applications

A Perspective on Continuous Flow Chemistry in the Pharmaceutical Industry

We report the high throughput analysis of reaction mixture arrays using methods and data handling routines that were originally developed for biological tissue imaging. Desorption electrospray ionization (DESI) mass spectrometry (MS) is applied in a continuous on-line process at rates that approach 104 reactions per h at area densities of up to 1 spot per mm2 (6144 spots per standard microtiter plate) with the sprayer moving at ca. 104 microns per s. Data are analyzed automatically by MS using in-house software to create ion images of selected reagents and products as intensity plots in standard array format. Amine alkylation reactions were used to optimize the system performance on PTFE membrane substrates using methanol as the DESI spray/analysis solvent. Reaction times can be <100 μs when reaction acceleration occurs in microdroplets, enabling the rapid screening of processes like N-alkylation and Suzuki coupling reactions as reported herein. Products and by-products were confirmed by on-line MS/MS upon rescanning of the array.

/pdf/high-throughput-reaction-screening-using-desorption-2zdonfvzfu.pdf

High throughput reaction screening using desorption electrospray ionization mass spectrometry

Ionic reactions in bulk solution generally occur relatively slowly, and the course of reaction can be followed by on-line monitoring using, for example, electrospray ionization mass spectrometry (MS). In another approach, ionic reactions occurring in confined volumes can be studied with a focus on increasing reaction rates upon reduction in solution volume (e.g., by solvent evaporation from small droplets). Such a situation is encountered in ambient ionization MS, which involves the ionization of samples in their native state without significant sample preparation. Reagents can be included in the spray solvents used in ambient ionization and rapid derivatization reactions can accompany ionization. These latter experiments form the topic of this review. Emphasis is on their value in chemical analysis, but the products of these reactions can also be collected easily and form the basis for small-scale synthesis.

Beyond the flask: Reactions on the fly in ambient mass spectrometry

The analytical performance and a suggested mechanism for zero volt paper spray using chromatography paper are presented. A spray is generated by the action of the pneumatic force of the mass spectrometer (MS) vacuum at the inlet. Positive and negative ion signals are observed, and comparisons are made with standard kV paper spray (PS) ionization and nanoelectrospray ionization (nESI). While the range of analytes to which zero volt PS is applicable is very similar to kV PS and nESI, differences in the mass spectra of mixtures are interpreted in terms of the more significant effects of analyte surface activity in the gentler zero volt experiment than in the other methods due to the significantly lower charge. The signal intensity of zero volt PS is also lower than in the other methods. A Monte Carlo simulation based on statistical fluctuation of positive and negative ions in solution has been implemented to explain the production of ions from initially uncharged droplets. Uncharged droplets first break up due to aerodynamics forces until they are in the 2-4 μm size range and then undergo Coulombic fission. A model involving statistical charge fluctuations in both phases predicts detection limits similar to those observed experimentally and explains the effects of binary mixture components on relative ionization efficiencies. The proposed mechanism may also play a role in ionization by other voltage-free methods.

https://www.dstuns.iitm.ac.in/listpdf/333.pdf

Zero Volt Paper Spray Ionization and Its Mechanism.

Thin film formats are used to study the Claisen-Schmidt base-catalyzed condensation of 6-hydroxy-1-indanone with substituted benzaldehydes and to compare reaction acceleration relative to bulk Acceleration factors relative exceeded 103 initially and were on the order of 102 at steady state, in spite of the fact that the confined volume reaction was not electrostatically driven Substituent effects were muted compared to those in the corresponding bulk and microdroplet reactions and it is concluded that the rate-limiting step at steady state is reagent transport to the interface Conditions were found that allowed product deposition from the thin film to occur continuously as reaction mixture was added and as solvent evaporated Yields of 74% and production rates of 98 mg/hour were reached in a very simple experimental system which could be multiplexed to greater scales

Reaction Acceleration in Thin Films with Continuous Product Deposition for Organic Synthesis

RATIONALE
This paper reports the development of arrays of capillary-based low-temperature plasma (LTP) probes for direct sample analysis. These probe arrays allow a higher surface area to be analyzed, increasing the throughput in large sample analysis. Validation of these arrays was performed on illicit, cathinone-based drugs marketed as 'bath salts'.

METHODS
LTP arrays consisting of 1, 7, and 19 probes were constructed with quartz capillaries and held together with silver epoxy resin adhesive. Three drugs, mephedrone, methylone and methylenedioxypyrovalerone, were analyzed with each plasma ion source and an ion trap mass spectrometer in full MS and in MS/MS positive ion mode. Chemical and thermal footprints were determined for each source. A reactive probe design was used to inject trifluoroacetic anhydride directly into the plasma stream for on-line derivatization.

RESULTS
Small LTP probes and bundled arrays provide low picogram level limits of detection for mephedrone, methylone and methylenedioxypyrovalerone. Bundling the probes together in larger arrays increases the surface area analyzed by a factor of ten, while maintaining surface temperatures below 40 °C. Selectivity towards mephedrone and methylone was increased using trifluoracetylation under ambient ionization conditions.

CONCLUSIONS
Low-temperature plasma ionization sources allow rapid detection of illicit 'bath salt' drugs in low amounts. The sources have a larger sampling area that allows faster detection of each analyte, and selectivity towards the selected drug is enhanced by adding reagents directly into the plasma stream. Copyright © 2012 John Wiley & Sons, Ltd.

Michael Wleklinski

Papers

High throughput reaction screening using desorption electrospray ionization mass spectrometry

Beyond the flask: Reactions on the fly in ambient mass spectrometry

Zero Volt Paper Spray Ionization and Its Mechanism.

Reaction Acceleration in Thin Films with Continuous Product Deposition for Organic Synthesis

Arrays of low‐temperature plasma probes for ambient ionization mass spectrometry