On Jan. 3, 2025, scientists from Scripps Research reported that by using computer modeling to predict chemical reactions, they were able to synthesize 25 variations of a plant compound that could treat brain diseases. Among the hundreds of thousands of chemical compounds produced by plants, some may hold the key to treating human ailments and diseases. But recreating these complex, naturally occurring molecules in the lab often requires a time-consuming and tedious trial-and-error process.

Chemists from Scripps Research have shown how new computational tools can help them create complex natural compounds in a faster and more streamlined way. They used their approach to synthesize 25 different picrotoxanes, compounds which are originally found in plants and have the potential to alter pathways in the brain.

Picrotoxanes bind to the same brain receptors targeted by the anxiety and sleep medication Valium. Scripps researchers were struggling to synthesize picrotoxanes and turned to advanced computer modeling to predict new ways to create picrotoxanes from basic chemical building blocks. They first generated a virtual library of possible intermediate compounds that could be formed during the synthesis of picrotoxanes. Then, they used a model known as Density Functional Theory (DFT) to analyze the behavior of these intermediates, flagging those that were likely to both succeed and quickly lead to neuroactive compounds.

When the group tested five picrotoxane synthesis pathways suggested by the modeling — three that were predicted to succeed and two predicted to fail — all five outcomes were correct. The researchers planned to continue testing the 25 picrotoxanes they can now produce to see how they impact mammalian biology. The study was published in Nature.