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Binding and Activation of Serotonergic G-Protein Coupled Receptors by the Multimodal Antidepressant Vortioxetine

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  • Lucy Kate Ladefoged
  • ,
  • Rebekka Koch
  • ,
  • Philip C. Biggin, University of Oxford
  • ,
  • Birgit Schiøtt

G-protein coupled receptors (GPCRs) are important pharmacological targets. Despite substantial progress, important questions still remain concerning the details of activation: how can a ligand act as an agonist in one receptor but as an antagonist in a homologous receptor, and how can agonists activate a receptor despite lacking polar functional groups able to interact with helix 5 as is the case for the related adrenergic receptors? Studying vortioxetine (VXT), an important multimodal antidepressant drug, may elucidate both questions. Herein, we present a thorough in silico analysis of VXT binding to 5-HT1A, 5-HT1B, and 5-HT7receptors and compare it with available experimental data. We are able to rationalize the differential mode of action of VXT at different receptors, but also, in the case of the 5-HT1Areceptor, we observe the initial steps of activation that inform about an activation mechanism that does not involve polar interaction with helix 5. The results extend our current understanding of agonist and antagonist action at aminergic GPCRs.

Original languageEnglish
JournalACS Chemical Neuroscience
Pages (from-to)1129-1142
Number of pages14
Publication statusPublished - Apr 2022

Bibliographical note

Publisher Copyright:
© 2022 by the authors.

    Research areas

  • 5-HT, GPCR, serotonin, vortioxetine, STRUCTURAL INSIGHTS, CRYSTAL-STRUCTURE, PARAMETERS, PREDICTION, 5-HT7, TOLERABILITY, 5-HT1A, DYNAMICS, 5-HT1B, COUPLED RECEPTORS, FORCE-FIELD, LIGAND, TOOL, Piperazines/pharmacology, Vortioxetine/pharmacology, Receptors, G-Protein-Coupled, Antidepressive Agents/pharmacology, Serotonin/metabolism

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