Jesús Angulo, head researcher at the Institute of Chemical Research in Spain, is part of an international team that has developed a new way to study how drug molecules interact with ion channels directly inside living cells. Their work, carried out with colleagues from the University of East Anglia and the Quadram Institute, offers a practical route for engineers and scientists working to design therapeutics for conditions linked to membrane proteins.
Monaco, S., Browne, J., Wallace, M., Angulo, J., & Stokes, L. (2025). On-Cell Saturation Transfer Difference NMR Spectroscopy on Ion Channels: Characterizing Negative Allosteric Modulator Binding Interactions of P2X7. Journal of the American Chemical Society, 147(36), 32400–32411. https://doi.org/10.1021/jacs.5c02985
Ion channels sit within the cell membrane and regulate the flow of ions, supporting processes such as nerve signaling, muscle contraction, and immune response. Because disruptions in their activity are associated with neurological disorders, metabolic diseases, cardiovascular conditions, and certain cancers, ion channels are considered important drug targets. However, conventional techniques for studying how potential drugs bind to these proteins often require isolating and purifying the channels. That step can change their structure and behavior, which makes it difficult to understand how a drug will actually work inside a living cell.
Jesús Angulo from University of Seville stated,
“Until now, studying how drugs interacted with these proteins required isolating them, a technically complex process that can alter their behavior. Our technique, based on nuclear magnetic resonance, allows us to study these interactions in living cells, which provides more biologically relevant information.”
The new technique adapts Saturation Transfer Difference Nuclear Magnetic Resonance, a method typically used with purified proteins, for use directly on living mammalian cells that express the ion channel of interest. Instead of needing protein purification, researchers grow cells engineered to overproduce the P2X7 ion channel, expose them to small drug molecules, and use NMR to detect which parts of each molecule physically contact the channel. These experiments take less than an hour and require far less preparation compared to traditional structural studies.
The team validated the method by examining two well-studied P2X7 antagonists and by testing the approach across different species variants of the receptor. They found that the NMR signatures corresponded well with known pharmacological data, which suggests that the technique provides reliable information about how strongly and where the compounds bind. Because the ion channel remains in its natural membrane environment, the results are more representative of real physiological interactions.
To support the experimental work, the researchers used computational modeling tools to evaluate possible three-dimensional drug–protein binding arrangements. Software developed at the Institute of Chemical Research allowed them to compare these models directly with the NMR data. This helped confirm which predicted binding modes align with what actually happens on the surface of living cells. According to the research team, this blend of modeling and experimental measurement creates a clearer, more practical framework for early-stage drug design.
P2X7, the ion channel used in the study, is involved in processes related to depression, some autism-spectrum conditions, chronic inflammation, and certain cancers. By identifying the precise molecular contacts between these antagonists and the channel, the researchers demonstrated how the technique can guide efforts to refine or redesign molecules for better therapeutic performance. The approach offers a way to examine membrane proteins that are difficult to crystallize or characterize using structural biology methods that require extensive sample preparation.
Although the method does not replace high-resolution techniques such as cryo-electron microscopy or X-ray crystallography, it fills a gap between computational predictions and laboratory validation. Its speed and relative simplicity may make it especially useful for screening new compounds or iterating on early drug candidates. The researchers believe that this live-cell NMR workflow could become a standard tool for mapping structure–activity relationships for many types of membrane proteins, not only ion channels.
Angulo describes the interaction between the drug and the protein as similar to understanding how a key fits into a lock. The challenge is not only identifying the right key but also understanding the orientation and motion needed for it to work. The team’s method provides a way to observe these details directly in living cells, rather than inferring them from isolated components. This offers a more accurate picture of how a drug behaves under realistic biological conditions.
As engineering and life-science research continues to move toward integrated, multi-modal approaches, methods like this one help bridge the gap between structural biology, computational modeling, and practical drug-development workflows. The study represents a step forward in designing more targeted therapies for complex diseases and highlights how engineering principles can support advances in modern biomedical research.
Adrian graduated with a Masters Degree (1st Class Honours) in Chemical Engineering from Chester University along with Harris. His master’s research aimed to develop a standardadised clean water oxygenation transfer procedure to test bubble diffusers that are currently used in the wastewater industry commercial market. He has also undergone placments in both US and China primarely focused within the R&D department and is an associate member of the Institute of Chemical Engineers (IChemE).
