New technique revolutionizes the design of drugs that target ion channels

An international team involving the Institute of Chemical Research, a joint centre of the University of Seville and the Spanish National Research Council, has developed a new technique that will accelerate the design of drugs that target ion channels, a type of cell membrane protein involved in numerous diseases, ranging from psychiatric disorders to various types of cancer.

The research, carried out in collaboration with the University of East Anglia and the Qadram Institute (both in the United Kingdom), has been published in the Journal of the American Chemical Society.

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

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."

Jesús Angulo, Institute of Chemical Research

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

The researchers believe their method could become a standard tool for structure-activity studies, which seek to understand how the chemical structure of a molecule relates to its pharmacological effect.

"Our technique could significantly accelerate the development of drugs that target ion channels and other membrane proteins, opening up new research possibilities in multiple areas, from neurological and cardiovascular diseases to metabolic and oncological diseases," says Leanne Stokes of the University of East Anglia.

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 Serena Monaco, a researcher at the Quadram Institute in Norwich.

In addition, thanks to software developed at IIQ-CSIC-US, the authors combined their experimental data with three-dimensional models of drug-receptor binding, generated using bioinformatics. This allowed them to validate which computer-generated models actually matched laboratory observations.

"The interaction between drug and protein can be compared to a lock and key: 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 more effectively," Angulo explains. "Bioinformatic models are essential to designing new drugs. Being able to validate three-dimensional computer models on living cells represents a new paradigm in the development of drugs targeting these proteins," the researcher concludes.

The study was funded by the UK's Biotechnology and Biological Sciences Research Council (BBSRC), UKRI Future Leaders Fellowship and the Spanish Ministry of Science and Innovation (together with the European Regional Development Fund ERDF).