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Binding of SEP-363856 within TAAR1 and the 5HT1A receptor: implications for the design of novel antipsychotic drugs

Molecular Psychiatry volume 27, pages 88–94 (2022)Cite this article

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Abstract

Current medications for schizophrenia typically modulate dopaminergic neurotransmission. While affecting positive symptoms, antipsychotic drugs have little clinical effect on negative symptoms and cognitive impairment. Moreover, newer ‘atypical’ antipsychotic drugs also have significant metabolic adverse-effects. The recent positive clinical trial of the novel drug candidate SEP-363856, which targets non-dopamine receptors (trace amine-associated receptor and the 5HT1A receptor), is a potentially promising development for the management of schizophrenia. In this perspective, we briefly overview the role of TAAR1 and the 5HT1A receptor in schizophrenia and explore the specific binding characteristics of SEP-363856 at these receptors. Molecular dynamics simulations (MDS) indicate that SEP-363856 interacts with a small, common set of conserved residues within the TAAR1 and 5HT1A ligand-binding domain. The primary interaction of SEP-363856 involves binding to the negatively charged aspartate residue (Asp1033.32, TAAR1; Asp1163.32, 5HT1A). In general, the binding of SEP-363856 within TAAR1 involves a greater number of aromatic contacts compared to 5HT1A. MDS provides important insights into the molecular basis of binding site interactions of SEP-363856 with TAAR1 and the 5HT1A receptor, which will be beneficial for understanding the pharmacological uniqueness of SEP-363856 and for the design of novel drug candidates for these newly targeted receptors in the treatment of schizophrenia and related disorders.

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Fig. 1: Comparative three-dimensional model of TAAR1 and the binding interactions of SEP-363856 identified by MD simulations.
Fig. 2: Key binding interactions of SEP-363856 within 5HT1A binding site identified by MD simulations.

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Acknowledgements

This research was undertaken with the assistance of resources from the National Computational Infrastructure (NCI), which is supported by the Australian Government. KJG and CJL acknowledge the support of the Monash Institute of Pharmaceutical Sciences Neuroscience and Mental Health Therapeutic Programme Area.

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Authors and Affiliations

  1. Discipline of Clinical Pharmacology, Adelaide, SA, Australia

    Pramod C. Nair & John O. Miners

  2. Flinders Health and Medical Research Institute (FHMRI) College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia

    Pramod C. Nair, John O. Miners & Ross A. McKinnon

  3. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Melbourne, VIC, 3052, Australia

    Christopher J. Langmead & Karen J. Gregory

  4. Department of Psychiatry, Monash University, Parkville, Melbourne, VIC, Australia

    David Copolov & Tarun Bastiampillai

  5. Department of Psychiatry, The University of Hong Kong University, Hong Kong, SAR, China

    Sherry Kit Wa Chan

  6. The State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong, China

    Sherry Kit Wa Chan

  7. Discipline of Psychiatry, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia

    Tarun Bastiampillai

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PCN and TB conceptualised the study, designed and performed experiments, analysed data, and wrote the manuscript. JOM, RAM, CJL, KJG, DC and SKWC contributed in data analysis and writing the manuscript.

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Nair, P.C., Miners, J.O., McKinnon, R.A. et al. Binding of SEP-363856 within TAAR1 and the 5HT1A receptor: implications for the design of novel antipsychotic drugs. Mol Psychiatry 27, 88–94 (2022). https://doi.org/10.1038/s41380-021-01250-7

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