New technique enables faster drug design for diseases linked to ion channels

An international team involving the Institute for Chemical Research, a joint center of the University of Seville and the Spanish National Research Council, has developed a new technique that will accelerate the design of drugs targeting ion channels, a type of cellular membrane protein implicated in many 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 UK), was 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 or immune response and their dysfunction is associated with numerous disorders, making them therapeutic targets of great interest.

“Until now, to study how drugs interact with these proteins, you have had to isolate them, a technically complex process that can change their behavior. Our technique, based on nuclear magnetic resonance, allows us to study these interactions in living cells, which provides more biologically relevant information,” explains Jesús Angulo from the Institute for Chemical Research.

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

The researchers believe their method could become a standard tool for structure-activity studies, which seek to understand the link between a molecule’s chemical structure and its pharmacological effect.

“Our technique could significantly accelerate the development of drugs targeting ion channels and other membrane proteins, opening up new research opportunities in multiple areas, from neurological and cardiovascular diseases to metabolic and oncological diseases,” explains Leanne Stokes from the University of East Anglia.

A new tool for pharmacological studies

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

“We have shown that we can identify, on living cells, which parts of the drug interact with the protein, which allows us to optimize these interactions; this is essential information for developing more effective and more specific drugs,” explains Serena Monaco, researcher at the Quadram Institute in Norwich.

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

“The interaction between drug and protein can be compared to a lock and a key: the membrane protein is the lock and our key is the drug. But we not only need to find the right key, but we also need to figure out how to insert it so that it opens more efficiently,” says Angulo.

“Bioinformatics models are essential for the design of 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,” concludes the researcher.