Scientists in the U.K. at the University of Birmingham have developed a novel technique, in collaboration with AstraZeneca, that can analyze how drug molecules bind to proteins in tissue samples. The method, which relies on mass spectrometry, could offer an improved route to drug discovery and development.
The new approach “Mass Spectrometry Detection and Imaging of a Non-Covalent Protein–Drug Complex in Tissue from Orally Dosed Rats,” described in Angewandte Chemie, enables researchers to use real tissue samples to assess which proteins the drug will bind to in the body and therefore how effective it is likely to be against the target. Being able to pinpoint the interaction between the drug and the protein can provide valuable insight to guide drug discovery.
“Here, we demonstrate detection by mass spectrometry of an intact protein–drug complex directly from liver tissue from rats that had been orally dosed with the drug. The protein–drug complex comprised fatty acid binding protein 1, FABP1, non-covalently bound to the small molecule therapeutic bezafibrate,” write the investigators.
“Moreover, we demonstrate spatial mapping of the [FABP1+bezafibrate] complex across a thin section of liver by targeted mass spectrometry imaging. This work is the first demonstration of in situ mass spectrometry analysis of a non-covalent protein–drug complex formed in vivo and has implications for early stage drug discovery by providing a route to target-drug characterization directly from the physiological environment.”
“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,” said Helen Cooper, PhD, lead researcher. “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.
“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.”
Mass spectrometry was the key methodology
In 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 specific fatty acid binding protein to which it attaches to form a complex.
The scientists were also able to measure both the varying amounts of this complex in the liver over time and how it spreads through the tissue.
According to AstraZeneca lead Richard Goodwin, PhD, senior director, imaging sciences, “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. This research will continue to support drug discovery and help accelerate us bringing new medicines to patients.”
Next steps for the research will include improving the sensitivity of the technique and extending it to other types of drug compounds. Looking further ahead, the team hopes it can be developed for use in human tissue, taken from biopsies. This would yield a greater understanding of why drugs work differently in different patients.
