A recent technique that may analyze how drug molecules bind to proteins in tissue samples could offer an improved path to drug discovery and development.

Researchers on the University of Birmingham developed the technique in collaboration with global biopharmaceutical company AstraZeneca. It uses mass spectrometry, an analytical tool commonly used for identifying the properties of molecules inside a sample.

A part of the early stages of drug discovery takes place in cell cultures, clusters of cells which can be grown within the laboratory, outside of their natural environment. Cell cultures enable the consequences of various compounds to be tested on specific biological targets involved in various diseases. Although this enables researchers to evaluate how the compounds act against the goal, it doesn’t capture the total effects of the physiological environment.

This recent technique, described in a paper published today [14 July 2022] in Angewandte Chemie, enables researchers to make use of real tissue samples to evaluate which proteins the drug will bind to within the body and subsequently how effective it’s prone to be against the goal.

Having the ability to pinpoint the interaction between the drug and the protein can provide helpful insight to guide drug discovery.

Often in early-stage drug discovery, measurements are taken outside of the physiological environment, so when researchers move onto testing drugs in tissue, they will fail because they’ve interactions that weren’t expected.

Identifying the drug protein interaction at this early stage, nevertheless, is incredibly hard. Using mass spectrometry on proteins is usually in comparison with making an elephant fly. What we have done is add an unsecured hat – the drug molecule – to the elephant, and measured the entire process. It’s exciting since it opens up the opportunity of having the ability to follow the route of a drug through the body. By identifying which proteins it interacts with scientists will find a way to predict at an earlier stage whether or not it’ll have the specified therapeutic effect.”

Professor Helen Cooper, Lead Researcher

Within the study, the researchers used tissue taken from the livers of rats dosed with 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 precise fatty acid binding protein to which it attaches to form a posh.

The researchers were also capable of measure each the various amounts of this complex within the liver over time, and the way it spreads through the tissue.

AstraZeneca lead Professor Richard Goodwin, Senior Director, Imaging Sciences said: “What is essential to delivering such progressive 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 exemplifies what might be done once we mix complementary skills to deal with significant unmet need. This research will proceed to support drug discovery and help speed up us bringing recent medicines to patients.”

Next steps for the research will include improving the sensitivity of the technique, and increasing it to other varieties of drug compounds. Looking further ahead, the team hopes it may be developed to be used in human tissue, taken from biopsies. This could yield a greater understanding of why drugs work in another way in several patients.

Source:

Journal reference:

Illes-Toth, E., et al. (2022) Mass Spectrometry Detection and Imaging of a Non-Covalent Protein-Drug Complex in Tissue from Orally-Dosed Rats. Angewandte Chemie. doi.org/10.1002/ange.202202075.