UVA scientists develop AI tools to accelerate new drug discovery

University of Virginia School of Medicine scientists have developed a bold new approach to drug development and discovery that could dramatically accelerate the creation of new medicines.

UVA's Nikolay V. Dokholyan, PhD, and colleagues have developed a suite of artificial intelligence-powered tools, called YuelDesign, YuelPocket and YuelBond, that work together to transform how new drugs are created. The centerpiece, YuelDesign, uses a cutting-edge form of AI called diffusion models to design new drug molecules tailored to fit their protein targets exactly, even accounting for the way proteins flex and shift shape during binding.

A companion tool, YuelPocket, identifies exactly where on a protein a drug can attach, while YuelBond ensures the chemical bonds in designed molecules are accurate. Together, the approach is poised to improve both how new drugs are designed and how quickly and efficiently existing drugs can be evaluated for new purposes.

Think of it this way: Other methods try to design a key for a lock that's sitting perfectly still, but in your body, that lock is constantly jiggling and changing shape. Our AI designs the key while the lock is moving, so the fit is much more realistic. This could make a real difference for patients with cancer, neurological disorders and many other conditions where we desperately need better drugs targeting these wiggly proteins but keep hitting dead ends."

Nikolay V. Dokholyan, PhD, UVA's Department of Neurology

The pitfalls of drug development

The average cost of developing a new drug has been estimated to reach or exceed $2.6 billion, and almost 90% of new drugs fail when they reach human testing. That is due, in no small part, to the difficulty of predicting how molecules in a drug will interact, or bind, with their targets in the body. If a molecule doesn't bind exactly as intended, at exactly the right spot, the drug won't work, or could have unwanted, harmful side effects.

Artificial intelligence has helped address this problem, greatly accelerating drug design, but Dokholyan's work takes it to the next level. His YuelDesign overcomes limitations of the existing options by designing drug molecules while treating proteins as flexible, dynamic structures, not the rigid and frozen snapshots used by other methods. This is critical because proteins often change shape when a drug binds to them, a phenomenon known as "induced fit." Ignoring this flexibility can lead to drugs that look promising on a computer screen but fail in reality.

Dokholyan and his team designed YuelDesign specifically to overcome this problem. Using advanced AI "diffusion models," the technology simultaneously generates both the protein pocket structure and the small molecule that can slot into it – the key that will turn the lock, allowing both to adapt to each other during the design process.

A companion tool, YuelPocket, uses graph neural networks to identify precisely where on a protein a drug should bind, even on predicted protein structures from existing tools such as AlphaFold. "Most existing AI tools treat the protein as a frozen statue, but that's not how biology works. Our approach lets the protein and the drug candidate evolve together during the design process, just as they would in the body," said researcher Dr. Jian Wang. "We showed, for example, that when designing molecules for a well-known cancer-related protein called CDK2, only YuelDesign could capture the critical structural changes that happen when a drug binds."

Mapping out protein pockets is critical to "virtually every aspect of modern development," the researchers note in a new scientific paper outlining their YuelPocket testing. The promising results have Dokholyan hopeful that the technology can reduce drug development costs, improve the success rate of new drug candidates and accelerate how quickly new treatments and cures can reach patients. (Accelerating how quickly lab discoveries can be turned into medicines to benefit patients is the primary mission of UVA's new Paul and Diane Manning Institute of Biotechnology.)

"Our ultimate goal is to make drug discovery faster, cheaper and more likely to succeed, so that promising treatments can reach patients sooner," Dokholyan said, adding that he wants to "democratize" drug discovery by putting new tools at scientists' fingertips. "We've made all of our tools freely available to the scientific community. We want researchers anywhere in the world to be able to use them to tackle the diseases that matter most to their patients."

Findings published

Dokholyan and his team have described the development and results of these tools in papers in the scientific journals PNAS, JCIM and Science Advances. The research team includes Wang, Dong Yan Zhang, Shreshty Budakoti and Dokholyan. The scientists have no financial interest in the work.

The research has been supported by the National Institutes of Health, grant 1R35 GM134864; the National Science Foundation, grant 2210963; the Huck Institutes of the Life Sciences; and the Passan Foundation.