By Morgan Nwanguma
Researchers from the University of Oklahoma have developed an innovative technique that could revolutionize drug discovery and lower the costs of pharmaceutical development.
Published in the Journal of the American Chemical Society, their method allows for the insertion of a single carbon atom into drug molecules at room temperature in a safe and sustainable way. This added carbon atom acts as a flexible site for further chemical modifications, enabling scientists to boost molecular diversity without disrupting delicate molecular structures.
Nitrogen atoms and nitrogen-based rings—known as heterocycles—are essential components in many medications. Led by OU Presidential Professor Indrajeet Sharma, the team discovered how to subtly alter these structures by introducing one carbon atom using a highly reactive compound called sulfenylcarbene. This process, known as skeletal editing, offers a powerful tool for transforming existing molecules into promising new drug candidates.
“By selectively adding one carbon atom to these existing drug heterocycles in the later stages of development, we can change the molecule’s biological and pharmacological properties without changing its functionalities,” he said.
“This could open uncharted regions of chemical space in drug discovery.”
Earlier approaches to this type of chemical modification relied on reagents that were often explosive, had limited compatibility with various functional groups, and raised serious safety concerns for large-scale use. In contrast, Sharma’s team has developed a bench-stable reagent that produces sulfenylcarbenes under mild, metal-free conditions at room temperature—achieving reaction yields as high as 98%. By avoiding metal catalysts, the method also reduces environmental and health risks, as many metals can be toxic to humans.
The researchers are now investigating how this breakthrough could transform DNA-encoded library (DEL) technology, a rapidly advancing tool in pharmaceutical research. DEL platforms enable scientists to quickly screen billions of small molecules for their ability to interact with disease-related proteins. The gentle, metal-free carbon insertion process developed by Sharma’s team is especially well-suited for DEL applications, as it operates in water-compatible solvents and under conditions mild enough to preserve DNA-linked molecules.
In collaboration with the Damian Young group at Baylor College of Medicine, the team is applying this strategy to perform precise skeletal editing within DELs. This could dramatically expand the chemical diversity and biological relevance of these libraries—addressing two major limitations in current drug discovery efforts.
“The cost of many drugs depends on the number of steps involved in making them, and drug companies are interested in finding ways to reduce these steps. Adding a carbon atom in the late stages of development can make new drugs cheaper. It’s like renovating a building rather than building it from scratch,” Sharma said. “By making these drugs easier to produce at large scale, we could reduce the cost of healthcare for populations around the world.”
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