Novel technique creates complex synthetic drug molecules

In a new study, scientists have demonstrated that they can transform simple chemicals into unique three-dimensional (3D) molecule structures resembling those found in nature. According to the researchers, these new structures have desirable properties for medicines. 

The team, from Scripps Research, US, discovered a potential drug lead for inflammatory disease during their study, which is now being investigated further. 

The researchers explained that ‘natural products’ tend to have complex, spherical 3D structures that bind precisely with molecules in the body, providing favourable drug attributes such as few side effects. However, synthetic molecules used in the early stages of drug discovery are typically flat, simple structures and are more likely to interact broadly with other molecules in the body, although are easy to obtain. 

For this reason, the researchers have been working for several years to create new tools for building better drug candidates than the flat molecules which dominate traditional drug-screening libraries. 

“We were able to start with flat molecules and use a single chemical operation to create much more complex shapes, such as those you would expect from metabolites of medicinal plants or marine organisms,” said Dr Ryan Shenvi, Scripps Research chemistry professor and senior author of the study. “In essence, we found a way to bridge the gap between the synthetic space and natural products, opening up a whole new realm to explore for potential drugs.”

Creating complex molecules

In 2015, the group tested simple chemical compounds known as butenolides, which are byproducts from the corn oil refining industry. Using an electronic complementarity process, they discovered that the compounds bonded almost instantaneously and their electron clouds joined together to form a new molecule with unexpected complexity. 

“Our next step was to find out if this reaction would work with other molecules that have different properties,” Shenvi said. “So, we built a small collection of these unusual constructs.”

Initial experiments showed that the electronic complementarity reaction has the same effect on many different types of flat synthetic molecules, transforming them into desirable 3D shapes that look like they could have been produced by a living cell.

After passing on their compound collection to a high-throughput screening facility, one of the molecules was immediately identified by other Scripps Research staff scientists for its ability act on a cell signaling pathway known as cGAS/STING. This pathway plays a key role in inflammation and is implicated in autoimmune disorders. The labs are now continuing to investigate the possible lead.

“We are now taking a step back to carefully analyse the chemistry and see if we can expand this kind of result to other areas,” Shenvi said. “Our goal is to blur the line between synthetic and natural product space and enable the discovery of new disease-relevant mechanisms.”   

The research appears in Nature Chemistry.