Membrane proteins are involved in a multitude of diseases, from psychiatric disorders to various types of cancer.

An international team has developed a new technique that will speed up the design of drugs targeting ion channels, a type of cell membrane protein involved in numerous diseases, from psychiatric disorders to various types of cancer.

The research is a collaboration between the University of East Anglia and the Quadram Institute, on the Norwich Research Park, and the Spanish National Research Council (CSIC).

“Our technique could significantly accelerate drug development targeting these proteins, opening up new research possibilities in multiple areas, from neurological and cardiovascular diseases to metabolic and oncological diseases,” says Leanne Stokes, from the University of East Anglia.

Ion channels are cell membrane proteins that regulate the passage of ions into the cell and are essential in processes as diverse as nerve transmission, muscle contraction and immune response. Their dysfunction is associated with numerous pathologies, making them therapeutic targets of great interest.

“Until now, in order to study how drugs interacted with these proteins, it was necessary to isolate them, a technically complex process that can alter their behaviour. Our technique, based on nuclear magnetic resonance (NMR), allows us to study these interactions in living cells, providing more biologically relevant information”, explains Jesús Angulo, from the Spanish National Research Council.

The new technique is faster, being based on experiments that last less than an hour, more economical and significantly simpler as it eliminates the need for complex sample manipulation processes.

“We believe our method could become a standard tool for structure-activity studies, and help understand how the chemical structure of a molecule relates to its pharmacological effect”, says Serena Monaco, from the Quadram Institute.

She adds : “This study is particularly important to me as it took place during my post doc years at the University of East Anglia and it has been a source of inspiration for my current research line, as a newly appointed Early Career Fellow at the Quadram Institute. I do believe that applying nuclear magnetic resonance to live cells, not only can help us to find new drugs, but also to better understand how the bacteria in our gut work in health and disease.”

A new tool for pharmacological studies

The new technique has been tested on P2X7 receptors, ion channels that are therapeutic targets for depression, certain autism spectrum disorders and some types of cancer.

“We have shown that we can identify, on living cells, which parts of the drug interact with the protein, allowing us to optimise these interactions. This is essential information for developing more effective and specific drugs,” says Jesús Angulo.

In addition, thanks to software developed at the Institute of Chemical Research (CSIC-University of Seville), the authors combined these experimental data with three-dimensional models of drug-receptor binding generated using bioinformatics, which allowed them to validate which computer-generated models actually matched what was observed in the laboratory.

‘The interaction between drug and protein can be compared to a key and a lock. The membrane protein is the lock and our key is the drug. But we not only have to find the right key, we also have to figure out how to insert it so that it opens better,’ explains CSIC researcher Jesús Angulo. ‘Using bioinformatics models is key to developing new drugs. Being able to validate these 3D computer models on living cells represents a new paradigm in the development of drugs targeting these proteins,’ he concludes.

The study is being published in the Journal of the American Chemical Society, and was funded by the Biotechnology and Biological Sciences Research Council (BBSRC), a UKRI Future Leaders Fellowship, and a Ministerio de Ciencia e Innovación grant co-funded by the European Regional Development Fund (ERDF).

Reference:

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. DOI: 10.1021/jacs.5c02985