Double Screening Identifies Four Compounds that Could Become Neurological Disease Therapies
Researchers at Roche’s innovation center in Basel, Switzerland, have identified four small molecule therapy candidates that target the neurotensin receptor, a protein believed to play a role in the development of Parkinson’s and other neurological disorders.
They used a double screening technique to narrow their list from thousands of possibilities to four.
Their study, “SPR-based fragment screening with neurotensin receptor 1 generates novel small molecule ligands,” was published in the journal Plos One and described in a press release.
Neurotensin is a small peptide, or protein component, that has a dual role. In the gut, it functions as a hormone. But after reaching the brain, it begins functioning as a neurotransmitter.
Because neurotensin regulates how the brain works, researchers have been studying whether it could be used as a target for potential neurological disease therapies.
Blocking the receptor could be a way to affect neurotensin’s function in the brain. An alternative to blocking it would be using neurotensin receptors to prevent its signaling. One receptor that scientists could develop a therapy around is the neurotensin receptor 1 (NTS1), which is found on nerve cells and neurological support cells known as glia.
Trying to develop a therapy around NTS1 has been challenging, however. The compounds that scientists have evaluated so far have either lacked the right chemical properties to inhibit the receptor or have been unable to cross the blood brain barrier and reach the brain.
Recent technological advances could help solve this problem. One improves the purity of soluble forms of neurotensin. Another makes it easier to screen for small molecules that have the right chemical properties to become a therapy.
Swiss researchers used a technology called Surface Plasmon Resonance (SPR) to do an initial screening of compounds that could regulate NTS1 activity.
SPR can evaluate several thousand compounds’ ability to bind to a receptor. It is unable to screen a type of molecule known as a ligand as well as scientists want, however. So the team coupled SPR with Nuclear Magnetic Resonance (NMR), which can do a far better job of detecting ligand-receptor interactions.
Led by Michael Hennig, CEO of leadXpro, the team used SPR to screen 6,369 compounds with the potential to become a therapy. The initial screening narrowed the list to 44. The researchers then selected eight to evaluate with NMR analysis. NMR showed that only four had the ability to bind to NTS1 the way the team wanted.
Additional computational analysis of the compounds’ structure offered insight into potential binding locations and interactions. The information could pave the way to the development of drugs that can treat neurological diseases by targeting neurotensin and NTS1 signals.
