Research Aims to Speed Up Drug Discovery Process

Protein-ligand interactions are fundamental to virtually all biological organisms and thus are the primary focus of pharmaceutical therapies. In the past, these interactions have been difficult to study due to limitations in available structural methods.

“Historically, to make drugs people have used compounds they know have the ability to perform a function or have an effect in the body and then do plenty of testing,” says Grant, principal investigator on the project. “Often, it’s a trial-and-error process. They don’t necessarily know how it works, they just know that it works.”

X-ray crystallography has allowed advances, but suffers from experimental limitations such as the bottleneck of crystallization and the inability to reveal dynamic structural states.

Grant’s research aims to address those limitations.

“We’re taking the initial information about the structure of the protein and combining it with solution X-ray scattering to determine the structures of other drugs or other compounds that are bound to the protein without having to go through the process of crystallization,” Grant says.

Solution scattering provides a mechanism for modeling the structure and dynamics of molecules in solution. However, current methods only provide low-resolution information, which is insufficient for characterizing atomic level interactions between ligands and proteins.

“I’ve developed an algorithm that combines crystallography with high-resolution solution scattering to determine the structure of the drug — how it’s bound to the protein — just from the solution scattering,” Grant says. “The idea is to help us understand how different ligands — or drugs — bind to proteins and drive a chemical reaction.”

That could potentially mean lower costs for drug companies in research and development.

“Solution scattering can theoretically be done at high throughput. For ligands, you can do it with at least moderate throughput,” Grant says. “Drug companies could screen a multitude of compounds and see the differences and changes of the solution scattering signal. Then, using my algorithm, help pinpoint where it binds and potentially how it binds.”

Grant says the research could be applied to other industries as well.

“It really applies to any ligand or any small atomic region of a molecule,” Grant says. “It’s not just drug discovery — it’s any fundamental biomolecular interactions.”

Grant is a scientist with BioXFEL (Biology with X-ray Free Electron Lasers), a National Science Foundation Science and Technology Center composed of eight U.S. research universities that is headquartered at UB.

Co-investigator is Andrew E. Bruno, senior programmer/analyst for UB’s Center for Computational Research.