Nanomolar chemistry enables 1500 experiments in a single day

Chemists at pharma giant Merck have conducted over 1500 chemistry experiments in under a day thanks to a miniaturised, high throughput automation platform they developed for identifying how synthetic molecules react under various conditions. The work could speed up drug discovery and provide chemists with a tool kit to explore new medicinal compounds.

The discovery of drug leads involves synthesising complex molecules and then screening them to identify how they react under various conditions including temperature and concentration. However, a typical screen might require 10mg of a compound to get just one data point, while state-of-the-art methods achieve the same with 1mg of material. Not only is this time consuming, but every milligram is precious in medicinal chemistry and the substrates needed to synthesise complex molecules are invariably in short supply.

Frustrated by these problems, which mean many molecules designed at Merck never get made or tested, Tim Cernak, Spencer Dreher and colleagues at Merck Research Laboratories in Rahway in the US, have found a solution. They combined the robotics used in biotechnology with high throughput mass spectrometry techniques to produce between 50 and 500 times more reaction data than existing methods. The team demonstrated their nanomole-scale method could execute 1536 chemistry experiments in less than a day with as little as 20µg of material per reaction.

'We are excited about how this technique could encourage the use of new chemistries in drug discovery,' says Dreher. 'Medicinal chemists tend to steer towards the reactions they can trust as there’s little time and material for reactions that might fail. We hope that, initially, the adoption of this approach can help medicinal chemists try out a new reaction on their complex substrate without burning up time and material.'

'You have to make the molecule to test your hypothesis of what it might do so you need a reaction that works – some reactions fail more than 50% of the time on drug-like substrates and that disconnect spurred 

Nanomolar chemistry enables 1500 experiments in a single day