Anti-nausea breakthrough for cancer patients
A 2.9 Å cryo-EM reconstruction of the serotonin receptor complex with the anti-nausea setron, alongside a close-up view of the drug-binding pocket and density map. [Case Western Reserve University School of Medicine].
US-based researchers have used cryo-electron microscopy to expose how widely-used anti-nausea drugs, used during cancer treatments, attach to a target protein in the gastrointestinal tract.
High-resolution images provide key details on how the so-called setron drugs attach into a binding pocket on the protein, offering clues into how anti-sickness drug design could be improved.
As Professor Sudha Chakrapani, of Physiology and Biophysics at Case Western Reserve University School of Medicine points out: "Cancer patients who have vomiting later in their treatment plans - delayed emesis - don't tend to respond to setrons... so there is a constant need for better drugs."
Drug improvement has stalled given the lack of models showing exactly how setrons attach to their target protein - the serotonin receptor - in the body.
However, the new study provides the highest-resolution images to date of a 'granisetron' setron settling inside the binding pocket of a serotonin receptor.
Using a Titan Krios for single particle cryo-electron microscopy, Chakrapani and colleagues tracked the receptor-drug interactions to 2.92 Å resolution
Images revealed that setrons use the same attachment site as the receptor's natural binding partner in the body, serotonin, but take a slightly different orientation that changes the receptor shape slightly.
The differences helped the researchers build a more precise model of how setrons work on a molecular level.
According to Chakrapani's colleague, Sandip Basak: "In the past, we didn't have the confidence to model the drug in its binding pocket. Now we can precisely do that. We can also watch the drug move in the pocket using molecular dynamics simulations."
"Identifying the binding pocket and the interactions that are most important, and the orientation of the drug in the binding pocket, lays the foundation for designing drugs that are going to be more efficient," adds fellow researcher, Yvonne Gicheru.
Research is published in Nature Communications.