The discovery and development of new drugs may be facilitated by the use of a novel method that can analyze the interactions of drug molecules with proteins in tissue samples. In cooperation with the major biopharmaceutical company AstraZeneca, University of Birmingham researchers created the method.
It employs mass spectrometry, a technique for analyzing data that is frequently used to determine the characteristics of molecules within a sample.
Cell cultures, collections of cells grown in a lab environment away from their natural environment, are used in the early stages of drug discovery. It is possible to test the impacts of multiple compounds on the precise biological targets involved in various diseases using cell cultures.
This enables researchers to evaluate how the compounds interact with the target, but it does not fully account for the physiological environment’s effects.
This novel technique enables researchers to evaluate which proteins the drug will bind in the body and, consequently, how effective it is likely to be against the target, using actual tissue samples. The study was published in the journal Angewandte Chemie on July 14th, 2022.
A precise understanding of the drug–protein interaction can help to direct the development of new drugs.
Usually in early-stage drug discovery, measurements are taken outside of the physiological environment, so when researchers move onto testing drugs in tissue, they can fail because they have interactions that were not expected. Identifying the drug protein interaction at this early stage, however, is incredibly hard. Using mass spectrometry on proteins is often compared to making an elephant fly.”
Helen Cooper, Professor and Lead Researcher, School of Biosciences, University of Birmingham
Helen Cooper adds, “What we’ve done is add an unsecured hat—the drug molecule—to the elephant, and measured the whole process. It’s exciting because it opens up the possibility of being able to follow the route of a drug through the body. By identifying which proteins it interacts with scientists will be able to predict at an earlier stage whether or not it will have the desired therapeutic effect.”
The study’s authors used liver tissue from rats given bezafibrate, a common medication for treating high cholesterol. They identified the drug molecule and the particular fatty acid binding protein to which it binds to form a complex using mass spectrometry on thin sections of tissue.
The amount of this complex in the liver changes over time, and the scientists were able to track its distribution throughout the tissue.
What is key 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 exemplifies what can be done when we combine complementary skills to address significant unmet need.”
Richard Goodwin, Senior Director and Lead Professor, Imaging Sciences, AstraZeneca
Richard Goodwin added, “This research will continue to support drug discovery and help accelerate us bringing new medicines to patients.”
The study’s next steps will involve increasing the method’s sensitivity and adapting it to work with different kinds of drug compounds. The team hopes to develop it for use in human tissue obtained from biopsies in the future. This would result in a better comprehension of why medications behave differently in various patients.
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.