The antidepressant drug vilazodone is an allosteric inhibitor of the serotonin transporter

Per Plenge, Dongxue Yang, Kristine Salomon, Louise Laursen, Iris E. Kalenderoglou, Amy H. Newman, Eric Gouaux, Jonathan A. Coleman () and Claus J. Loland ()
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Per Plenge: University of Copenhagen
Dongxue Yang: Oregon Health & Science University
Kristine Salomon: University of Copenhagen
Louise Laursen: University of Copenhagen
Iris E. Kalenderoglou: University of Copenhagen
Amy H. Newman: National Institutes of Health
Eric Gouaux: Oregon Health & Science University
Jonathan A. Coleman: Oregon Health & Science University
Claus J. Loland: University of Copenhagen

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract Depression is a common mental disorder. The standard medical treatment is the selective serotonin reuptake inhibitors (SSRIs). All characterized SSRIs are competitive inhibitors of the serotonin transporter (SERT). A non-competitive inhibitor may produce a more favorable therapeutic profile. Vilazodone is an antidepressant with limited information on its molecular interactions with SERT. Here we use molecular pharmacology and cryo-EM structural elucidation to characterize vilazodone binding to SERT. We find that it exhibits non-competitive inhibition of serotonin uptake and impedes dissociation of [3H]imipramine at low nanomolar concentrations. Our SERT structure with bound imipramine and vilazodone reveals a unique binding pocket for vilazodone, expanding the boundaries of the extracellular vestibule. Characterization of the binding site is substantiated with molecular dynamics simulations and systematic mutagenesis of interacting residues resulting in decreased vilazodone binding to the allosteric site. Our findings underline the versatility of SERT allosteric ligands and describe the unique binding characteristics of vilazodone.

Date: 2021
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DOI: 10.1038/s41467-021-25363-3

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