One of the most common types of medicine is a category called small-molecule drugs. This includes the pills you’re used to taking, such as ibuprofen, but the category covers drugs for everything from eczema to cancer.
However, when researchers want to create a new small-molecule drug to treat disease, the process is long and complex—and it starts with making the compound itself to test it.
A new breakthrough by University of Chicago chemists shows how to easily customize molecules by swapping carbon-oxygen pairs for nitrogen atoms. In some cases, the process can be reduced from 10 steps down to just one or two.
The team hopes the finding, published April 30 in Science, could accelerate drug discovery.
“This is another strong tool in the box for the goal of being able to imagine a molecule and then make it—to assemble a molecule as a wish,” said chemist Zining Zhang, a graduate student at UChicago and first author on the paper.
Structure matters
Creating molecules from scratch is hard. It’s not like reaching into a box of loose Lego bricks. It’s more like starting from a box of already partly assembled Lego builds and cobbling those together into the structure you want—with very strict rules about how and when you can take pieces apart.
The structure you’re making matters a lot. When you’re making a drug, tiny changes—like moving a single nitrogen atom—can have huge implications in the final product. That single atom could make the difference between a drug that latches onto the right proteins in the body and one that fails.
But when researchers want to test out different versions of a molecule, to see which one works best, they have to laboriously figure out how to build each new iteration.
“So the question we try to address is, can we find a quicker way to introduce many different structural variations that contain nitrogen atoms?” said Guangbin Dong, the Weldon G. Brown Professor of Chemistry at UChicago and senior author on the paper.
In this case, the scientists wanted to see whether they could figure out a way to easily swap in nitrogen atoms in place of carbonyl groups, a common feature of small molecules that consists of paired carbon and oxygen atoms.
Previously, the Dong lab found a way to more easily move these carbonyl groups around when making a new drug. But they also wanted to give researchers the ability to move nitrogen where needed.
“The location of the nitrogen is important because it is often the piece that interacts with the active site in your body, so we want to be able to move it easily,” explained Zhang.
The group was able to find a simpler method using an ingredient called NAHA, which grabs the carbonyl and cleaves its bond. Then, through a series of moves like choreographed dancers switching partners, the empty space gets filled with nitrogen.
The process is simple, effective and inexpensive, the scientists said. They also noted the design of the technique allows many different types of attachments, known as functional groups, to be compatible, even those that are normally tricky to successfully integrate.
“This was kind of a dream reaction,” said Zhang, “so it was really gratifying to see it work.”
Dong added the group plans to continue pursuing the direction.
“We’d like to be able to swap carbonyl to all of the possible important atoms,” he said.
The other authors on the paper were visiting undergraduate student Zhehan Liang and graduate student Rong Ye.
Citation: “Scanning nitrogen in sp3-rich scaffolds enabled by carbonyl-to-nitrogen atom swap.” Zhang et al,
Funding: National Institute of General Medical Sciences, Bristol Myers Squibb fellowship.
