Targeting new drugs for schizophrenia

Flinders University researchers have investigated how an antipsychotic drug currently in the development stage binds to its intended target, potentially paving the way for the design of better antipsychotics.

Schizophrenia is a highly complex mental health disorder affecting one percent of the world’s population, with few effective long-term treatments.

SEP-363856 or Ulotaront is an experimental antipsychotic, currently undergoing clinical trials for the treatment of schizophrenia and related disorders. Unlike many existing antipsychotic drugs, SEP-363856 is an agonist, stimulating certain receptors in the brain, rather than an antagonist, which switches them off.

Now a group of Flinders University researchers, including Dr Pramod Nair, Professor John Miners, Professor Ross McKinnon and Professor Tarun Bastiampillai, have played a key role in discovering how the drug candidate is able to recognise and interact with its intended target site in the brain, a protein called trace amine-associated receptor (TAAR1).

The Flinders University team, along with researchers at Monash University and the University of Hong Kong, employed the supercomputing and data services facility at The National Computational Infrastructure (NCI) in Canberra to model what happened to the receptor when it was exposed to SEP-363856.

Published in the Nature journal Molecular Psychiatry, the research found that the antipsychotic interacts with a unique set of residues that may play a prominent role in the selective binding of the drug to TAAR1 over other receptors.

Such deeper structural insights are valuable for developing effective targeted therapies with reduced off-target effects.

“Understanding how drugs and drug-like molecules interact with drug targets at an atomic level allows us to predict their binding interactions and provides a guide to the rational design of new therapeutic agents,” says lead author Dr Pramod Nair from Flinders University’s College of Medicine and Public Health.

“Using high-performance computing platforms allows us to rapidly predict such mechanisms, which would take several years if we were to do it in a lab.

“Understanding these processes in a short timeframe is valuable for developing effective therapeutics with reduced adverse reactions and a better scope towards personalised medicine.”

‘Binding of SEP-363856 within TAAR1 and the 5HT1A receptor: implications for the design of novel antipsychotic drugs’ by Pramod Nair, John Miners, Ross McKinnon, Christopher Langmead, Karen Gregory, David Copolov, Sherry Kit Wa Chan and Tarun Bastiampillai is published in the journal Molecular Psychiatry. DOI: 10.1038/s41380-021-01250-7

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College of Medicine and Public Health Research