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Using an IR sensor, researchers have analyzed which active agents affect protein structure and how long the effect lasts. The method they used could one day be applied to the quick and targeted development of drugs with fewer side effects.
Developed by researchers from Ruhr University Bochum in Germany, the new method provides information on structural changes to target proteins within minutes and can help narrow down the type of structural change.
The IR sensor was developed by Klaus Gerwert (left) and Jörn Güldenhaupt. Courtesy of Gerd Kock.
“The way an active agent affects the structure of its target protein has so far been analyzed using time-consuming and material-intensive methods, which may provide extremely detailed spatial information, but which don’t yield results until weeks or even months later,” said researcher Jörn Güldenhaupt.
The sensor is based on a crystal that is permeable to IR light. The protein is bound on its surface. IR spectra are recorded through the crystal while the surface is rinsed with solutions with or without any active agents. The sensor detects changes to the protein’s spectral area, which is structure-sensitive. If any changes occur, it can be deduced that the active agent has altered the shape of the protein.
Many drugs manipulate the metabolism of cells by inhibiting the activity of specific proteins. To this end, the drug molecule binds to the target protein. The active agent typically settles in the functional compartments, or binding pouches, of proteins. Following so-called conformational change in a target protein, new surface areas and binding pouches in the protein become accessible, and an active agent can be further adapted to match them. This process often results in a better selectivity of active agents, thus reducing side effects.
In collaboration with Merck, the team demonstrated the reliability of its method by analyzing the way two different active agent groups affected the heat shock protein HSP90, a protein folder that helps newly generated proteins in the cell to form the correct 3D structure. Tumor cells, because of their extremely active metabolism, require HSP90. Thus, HSP90-inhibiting active agents constitute an approach for the development of drugs that can stop tumor growth.
Researchers immobilized HSP90 on an ATR (attenuated total reflectance) crystal and investigated ligand-induced secondary structural change. Two specific binding modes of 19 drug-like compounds were analyzed. The conformational effects of the analyzed inhibitors were determined correctly for all compounds with existing X-ray data. Furthermore, the binding modes of 11 additional inhibitors were determined for the first time.
Researchers believe their work demonstrates the first systematic application of an IR-spectroscopy-based flow-through sensor for the label-free and time-resolved detection of ligand-induced conformational changes.
“Since our sensor acts as a flow system, we can rinse the active agents off the target protein after binding and, consequently, measure how the efficacy changes over time,” said researcher Klaus Gerwert.
The research was published in Angewandte Chemie International Edition (doi:10.1002/anie.201802603).READ MORE