Infrared Sensor As A New Method For Drug Development

Changes to the scaffold of proteins quickly indicate whether a drug is effective.

With an infrared sensor, biophysicists of the Ruhr-Universität Bochum (RUB) have succeeded in quickly and easily investigating which active ingredients influence the structure of proteins and how long this effect lasts. Prof. Dr. Klaus Gerwert and dr. Jörn Güldenhaupt was thus able to measure structural changes on the scaffold of proteins triggered by active agents in a time-resolved manner. In the future, their method could help to develop drugs with fewer side effects faster and more accurately. The team reported in the journal Angewandte Chemie on May 17, 2018, reports on the work carried out as part of the European Union-funded Innovative Medicines Initiative program in the Kinetics for drug discovery (K4DD) project.

Drugs can alter the structure of target proteins
The effect of many drugs is to influence the metabolism of cells by specifically inhibiting the activity of certain proteins. For this purpose, the drug molecule must bind to the respective target protein, wherein the drug usually sets in the pocket-like recessed functional areas of proteins.

For some drugs, binding to the target protein also changes the structure of the protein surface. Through such a so-called conformational change new surface areas and binding pockets are accessible, to which one can further customize an active ingredient. This often leads to a better selectivity of active ingredients and thus to fewer side effects.

New method allows fast measurement
"So far, the influence of an active substance on the structure of a target protein has been investigated with time-consuming and material-intensive methods that provide very detailed spatial information but only yield results after weeks to months," explains Jörn Güldenhaupt.

By contrast, the method developed by the Bochum researchers provides information about structural changes within minutes and can even limit the type of structural change.
The sensor is based on a transparent to infrared light crystal. The target protein is bound on its surface. Through the crystal, the infrared spectra are recorded, while simultaneously flushed solutions with or without active ingredient over the surface. The sensor detects changes in the structure-sensitive spectral region of the protein, the so-called amide region, which is characteristic of the framework of a protein. If there are changes here, it is clear that the drug has changed the protein form.

Example heat shock protein
How reliable the method is was demonstrated by the team in cooperation with the company Merck, which investigated the influence of two different groups of active ingredients on the heat shock protein HSP90. It is a folding helper that helps the cell's newly-created proteins to form the correct three-dimensional structure. Tumor cells need it because of their very active metabolism especially urgent. Inhibitory agents for HSP90 are an approach for drugs that inhibit tumor growth.

Binding time determines how often a drug must be taken
The speed with which a drug molecule dissolves again from the target protein corresponds to the duration that the drug also acts in the body. Active ingredients with a long complex lifetime remain bound to the target protein for a long time and therefore often have a long-lasting effect. For example, tablets containing such agents only need to be taken once a day and often have fewer side effects. "Since our sensor works as a flow-through system, we can rinse the active ingredients off the target protein after binding and thus also measure the time course of the efficacy," explains Klaus Gerwert.