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Medicinal Chemistry

Miniaturized technique maximizes search space for new drugs

Method optimizes reaction conditions and protein-binding affinity using a few milligrams of material

by Carmen Drahl
April 30, 2018 | A version of this story appeared in Volume 96, Issue 18

Reaction scheme illustrates conversion of one starting material to many compounds, simultaneously optimizing reaction conditions, building blocks, and protein binding affinity.
Credit: C&EN/Timothy Cernak/Shutterstock

For every new project, medicinal chemists face the same arduous task: multiple rounds of chemical synthesis and biological testing, all to optimize the binding interaction between a potential drug candidate and a protein of interest. Now, researchers at Merck report a way to accomplish that with only a few milligrams of starting material (Nature 2018, DOI: 10.1038/s41586-018-0056-8). The strategy merges miniaturized high-throughput synthesis with a technique that can assess protein-binding affinity in crude reaction mixtures. Compared with traditional synthesis, this method lets chemists explore more reaction conditions and building blocks, says Tim Cernak, who led the team and has since moved to the University of Michigan, Ann Arbor. Using a commercially available robot, the Merck team performed over 3,000 transformations typical of pharmaceutical research, such as Suzuki couplings. They tested reaction mixtures for binding affinity to kinase enzymes implicated in cancer, turning up a handful of compounds with excellent, low-nanomolar binding affinity. Merck has refined the technology and is using it routinely in active drug discovery programs, says Emma Parmee, the firm’s vice president and head of discovery chemistry.


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