New research gives scientists powerful drug discovery tool
new system for analysing how drugs bind to proteins, which could
speed up the delivery of potential new drugs and improve existing
ones.
The collaborative research is focused on getting a more accurate picture of human proteins, which are the target of most drugs. Understanding the nature of the interaction between a drug and a protein is one of the keys to drug research, because the exact placement of a drug can determine whether it enhances a natural biological function or counteracts it.
Researchers at Florida State University and Scripps Florida used a Fourier transform ICR mass spectrometer built around a 14.5-tesla superconducting magnet.
A tesla is a unit of measurement of a magnetic field's strength. To illustrate the magnet's relative strength, an MRI machine is 1.5 tesla, and a refrigerator magnet is 0.0025 tesla.
They used this technology to conduct a "molecular spray painting" experiment. Here the receptor protein with a drug stuck to it is dipped into a solvent called "heavy water" (deuterium oxide, or D2O).
In portions of the receptor that can exchange with heavy water (regions not involved in hydrogen bonding), the natural hydrogen atoms are gradually replaced by deuterium atoms, which increase the mass from 1 to 2 mass units.
Scientists then dissected the receptor and used the magnet to weigh pieces of it to see which segments of the receptor remain covered up by the drug.
The team saw the potential of probing human protein molecules with this spray-painting technique, but also recognised that the experiment was limited by several factors.
Each test that would have to be performed would take anywhere from one minute to several hours, and each measurement would be slow.
To ensure the reliability of the experiment, the process would need to be replicated twice more to validate the results, adding additional days to the process.
"By pairing the magnet lab's expertise in high-field research with Scripps' expertise in protein dynamics and drug development, we can create a kind of map that shows where drugs bind to the surface of proteins," said Alan Marshall, director of the lab's Ion Cyclotron Resonance (ICR) program and the Kasha Professor of Chemistry and Biochemistry at FSU.
"We can do that because our technology is the best way to generate highly accurate pictures of tiny amounts of protein molecules."
The paper published in Analytical Chemistry lays out the results of research to improve the technical aspects of the experiment. By utilising the high-field ICR magnet and its powerful spectrometer, coupled with a sample preparation robot, the scientists were able to extract data that show how the drug alters the dynamics of the receptor upon binding.
This application of the experiment can measure changes in a fraction of the time and show those changes over time.
"This research is important because it gives us a new and very powerful way to probe the interaction between drugs and proteins," said Patrick Griffin, professor of biochemistry and head of drug discovery at Scripps Florida.
"Because we've now solved many of the technical problems, this technique is sure to play an even larger role in understanding the mechanism of action of many classes of drugs."
Now that the data acquisition has been automated, the next step is automating the data analysis. The amount of data generated by the magnet's high-test mass spectrometer is staggering: 1 million data points every second.
To analyse the data by hand would take a month. With automated software being developed at the magnet lab, the analysis will take just a few minutes.
The work, which appears this week in the journal Analytical Chemistry, is the first published paper to result from a partnership between Scripps and a Florida university
