A new era of rationally designed antipsychotics

Sibley, David R.; Shi, Lei

doi:10.1038/d41586-018-02328-z

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26 February 2018

A new era of rationally designed antipsychotics

The ideal drugs for treating schizophrenia are postulated to selectively block the D2 dopamine receptor with optimum binding kinetics. The structure of D2 bound to an antipsychotic sheds light on how to design such drugs.

David R. Sibley⁰ &
Lei Shi¹

David R. Sibley
1. David R. Sibley is in the Molecular Neuropharmacology Section, National Institute of Neurological Disorders & Stroke, National Institutes of Health, Bethesda, Maryland 20892-3723, USA.
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Lei Shi
1. Lei Shi is in the Computational Chemistry and Molecular Biophysics Unit, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, USA.
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Schizophrenia is a disorder that involves hallucinations, delusions and cognitive impairment, and that affects nearly 1% of the global population¹. The mainstays of therapy have been drugs that block the activity of the D2 dopamine receptor (D2R), a member of the large G-protein-coupled receptor (GPCR) superfamily of membrane proteins. Unfortunately, most of these antipsychotic drugs come with a plethora of debilitating side effects, many of which are due to off-target interactions with other GPCRs. In a paper in Nature, Wang et al.² now report the crystal structure of D2R in complex with the antipsychotic drug risperidone. The structure reveals features that might be useful for the design or discovery of drugs that have greater selectivity for D2R than existing therapeutics, and consequently have fewer side effects.

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Nature 555, 170-172 (2018)

doi: https://doi.org/10.1038/d41586-018-02328-z

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