New technique could offer an improved route to drug discovery and development
A new technique that can analyze how drug molecules bind to proteins in tissue samples could offer an improved route to drug discovery and development.
Researchers from the University of Birmingham developed the technique in collaboration with global biopharmaceutical company AstraZeneca. It uses mass spectrometry, an analytical tool commonly used to identify the properties of molecules in a sample.
Some of the early stages of drug discovery take place in cell cultures, clusters of cells grown in the laboratory, outside of their natural environment. Cell cultures make it possible to test the effects of different compounds on specific biological targets implicated in various diseases. While this allows researchers to assess how compounds act against the target, it does not capture all of the effects of the physiological environment.
This new technique, described in an article published today [14 July 2022] in Angewandte Chemie, allows researchers to use real tissue samples to assess which proteins the drug will bind to in the body and therefore its effectiveness against the target.
Being able to identify the drug-protein interaction can provide valuable information to guide drug discovery.
Usually, in the early stage of drug discovery, measurements are taken outside of the physiological environment, so when researchers move on to testing drugs in tissues, they may fail because they have unexpected interactions.
However, identifying the drug-protein interaction at this early stage is incredibly difficult. Using mass spectrometry on proteins is often compared to making an elephant fly. What we did was add an insecure hat – the drug molecule – to the elephant, and measure the whole process. It’s exciting because it opens up the possibility of being able to follow the journey of a drug through the body. By identifying the proteins it interacts with, scientists will be able to predict at an earlier stage whether or not it will have the desired therapeutic effect.”
Professor Helen Cooper, Principal Investigator
In the study, the researchers used tissue taken from the livers of rats given bezafibrate, a drug commonly used to treat high cholesterol. They used mass spectrometry on thin sections of tissue to detect the drug molecule and the specific fatty acid-binding protein it binds to to form a complex.
The researchers were also able to measure both the varying amounts of this complex in the liver over time and how it spreads through the tissues.
AstraZeneca Senior Professor, Richard Goodwin, Senior Director, Imaging Sciences, said, “Critical to delivering such innovative science is sustained collaboration between academic leaders and industry partners. This research builds on a long-standing collaboration between AstraZeneca and the University of Birmingham, and illustrates what can be done when we combine complementary skills to address significant unmet needs. This research will continue to support drug discovery and help us accelerate the delivery of new drugs to patients.
Next steps in research will include improving the sensitivity of the technique and extending it to other types of drug compounds. In the longer term, the team hopes that it can be developed for use in human tissue, taken from biopsies. This would provide insight into why drugs work differently in different patients.
Illes-Toth, E., et al. (2022) Mass spectrometric detection and imaging of a non-covalent protein-drug complex in the tissues of orally administered rats. Angewandte Chemie. doi.org/10.1002/ange.202202075.