- A new technique holds promise for high speed reaction screening while using minute amounts of chemicals (low µg level).
- It provides information valuable in scaled-up synthesis, including solvent and pH optimization.
- It can reduce analysis time for 100,000 reactions from two months to about a day.
Researchers at Purdue University have developed a methodology that can make drug discovery process, known as high-throughput screening, 10 times faster than previously used techniques.
Pharmaceutical discovery mainly depends on screening massive numbers (libraries) of compounds against biological targets of therapeutic interest. There are estimated 1060 drug-like molecules of pharmaceutical interest and more than 107 possible reaction states for each metal-catalyzed reaction used to create a drug scaffold.
The high-throughput library screening area hit a plateau, where the quickest screen took nearly 8 seconds per target. This new research that reports a reduced time factor of 10 can potentially do library screens within days (which usually takes months). The objective of the study is to rationalize organic synthesis.
High-Throughput Screening
High-Throughput Screening leverages automation to rapidly assay the biochemical activity of a vast number of drug-like compounds. It’s very helpful for discovering ligands for receptors, ion-channels, enzymes and other pharmacological targets.
It utilizes robotics, data processing software, sensitive detectors, liquid handling instruments to quickly carry out millions of genetic and pharmacological tests. This enables researchers to identify antibodies or genes, active compounds that modulate a specific biomolecular pathway – extremely helpful in discovering drugs.
Desorption Electrospray Ionization
To develop a faster screening process, the researchers combined robotic sampling technologies with Desorption Electrospray Ionization (DESI) Mass Spectrometry (MS), which is a method for creating ions from solid samples.
High throughput reaction screening experiment workflow with DESI-MS
DESI is an ambient ionization method that uses charged microdroplets to extract analytes from complex samples. It does so with 200 micrometer spatial resolution with rapid data collection (less than 1 second per spot).
Originally built for biological tissue imaging, DESI sprays electrically charged particles at a sample, through which ions are created, gathered and later examined in a standard mass spectrometer.
Reference: RSC | doi:10.1039/c7sc04606e | Purdue University
Basically, what they are doing is spraying a solvent on a sample mixture and building a new product, which is seen in a splashed droplet. It allows scientists to carry out a reaction and examine the product in a single step, in one second.
Reaction and MS product analysis of reaction mixtures in microtiter plate format
As we’ve mentioned, this new technique analyzes product outcomes in reaction droplets within one second. It is capable of reducing analysis time for 100,000 reactions from two months to about a day. The use of high throughput experimental methods in guiding scalable synthesis like continuous flow reactors, has the potential to significantly enhance the speed at which an configured process can be achieved at scale.
On the other hand, the conventional process of reaction optimization, route design and scaling can take years to implement for various target compounds.
Technical Details
More specifically, DESI-MS is applied in a continuous on-line process at 10,000 reactions per hour at 1 spot per millimeter square area density, with the sprayer moving at 10,000 microns per second.
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To build ion images of given reagents and products, mass spectrometry examines data automatically using in-house software. Researchers used amine alkylation reactions to tweak the system performance on poly tetrafluoroethylene membrane (PTFE) substrate using methanol as analysis solvent or DESI spray.
Reaction acceleration takes place in microdroplets, enabling quick screening of processes such as Suzuki coupling and N-alkylation reactions – all under less than 100 microseconds.
