UCLA Research Improves Molecular Probe For Drug Discovery

Findings
A UCLA-led international research collaboration unveiled a new technology that may help scientists better understand how small molecules, including many drugs, bind to proteins. The invention works with an existing lab method called photo-crosslinking. Leaving behind a clean, uniform chemical signature, the technology allowed the team to directly compare how different molecules compete for the same binding site on a protein, all in a single experiment. Because most small-molecule drugs act by binding to specific protein targets, finding precisely where these molecules bind is a major benefit for drug discovery.

As proof of concept, the team analyzed the activity of dasatinib and ascinimib, two cancer drugs that target different sites on the same protein, a type of enzyme called a kinase that, when mutated, causes leukemia. The results coincided with known interactions for each drug and revealed previously unknown interactions. The newer drug, ascinimib, which has a more favorable safety profile and fewer side effects, showed fewer off-target kinase interactions.

Background
When scientists search for new drugs, one key challenge is figuring out exactly where a molecule binds to a protein and whether it’s hitting the right functional spot. Photo-crosslinking, first introduced in 1969, helps by attaching a special chemical tag to a molecule. When exposed to UV light, the tag locks in place wherever it lands on a protein. However, one longstanding challenge has been that chemical tags left behind after UV crosslinking are structurally messy and inconsistent between different molecules, making apples-to-apples comparisons unreliable.

Method
The key to the UCLA-led team’s new technology, called SEE-CITE, is giving the molecule being studied the ability to detach from its payload so that each tagged molecule leaves behind a consistent calling card. This makes possible quantitative measurements and comparisons of how strongly different molecules engage a given binding site. The team also upgraded a widely used software tool to better interpret the complex data this method generates.

Impact
Overall, SEE-CITE presents a more precise and reliable tool for mapping where molecules bind to proteins. The technology thus has potential for studying the mechanisms that underlie health and disease, as well as for drug discovery in cancer, cholesterol regulation, metabolic liver disorders and more.

The method may enable scientists to identify new therapies, reveal previously unrecognized biological activity of existing compounds and characterize the details of how drugs interact with their targets. It also offers a practical approach for evaluating off-target binding, helping to anticipate and mitigate potential side effects.

For the UCLA research group behind the study, SEE-CITE is another step in their mission to develop technologies that enable scientists to comprehensively profile all interactions underlying health and disease.