Developed in collaboration with the IIQ-CSIC-US, it enables the analysis of the interaction between the drug and the protein in living cells under conditions similar to those found in the body
An international team, including researchers from the Spanish National Research Council (CSIC), has developed a new technique that will speed up the design of drugs targeting ion channels, a type of cell membrane protein implicated in numerous diseases, ranging from psychiatric disorders to various types of cancer. The research — a collaboration between the Spanish National Research Council (CSIC), 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 and are fundamental to processes as diverse as nerve transmission, muscle contraction and the immune response. Their dysfunction is associated with numerous diseases, making them therapeutic targets of great interest.
“Until now, 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, allows us to study these interactions in living cells, which provides biologically more relevant information,” explains Jesús Angulo, from the Institute of Chemical Research (a joint centre of the CSIC and the University of Seville).
The new technique is faster — it relies on experiments lasting less than an hour —, more cost-effective, and significantly simpler, as it eliminates the need for complex preliminary processes such as protein purification or sample handling.
The researchers believe that their method could become a standard tool for structure-activity studies, which aim to understand how a molecule’s chemical structure relates to its pharmacological effect.
“Our technique could significantly accelerate the development of drugs targeting ion channels and other membrane proteins, opening up new research possibilities in a wide range of areas, from neurological and cardiovascular diseases to metabolic and oncological conditions,” says Leanne Stokes of the University of East Anglia in the UK.
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 demonstrated that we can identify, in living cells, which parts of the drug interact with the protein, enabling us to optimise these interactions; this is essential information for developing more effective and specific medicines,” says Serena Monaco, a researcher at the Quadram Institute in Norwich, also in the UK.
Furthermore, using software developed at the IIQ-CSIC-US, the authors combined these experimental data with three-dimensional models of drug-receptor binding generated using bioinformatics, enabling them to validate which computer-generated models actually matched what was observed in the laboratory.
“The interaction between a drug and a protein can be compared to a key and a lock. The membrane protein is the lock and our key is the drug. But we don’t just have to find the right key; we also have to work out how to insert it so that it opens the lock more effectively,” explains Angulo. “Bioinformatic models are key to designing new drugs. Being able to validate three-dimensional computer models using live cells represents a new paradigm in the development of drugs targeting these proteins,” concludes the CSIC researcher.