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

Lucy Kate Ladefoged, Rebekka Koch, Philip C. Biggin, Birgit Schiøtt*

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Abstract

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
Volume13
Issue8
Pages (from-to)1129-1142
Number of pages14
ISSN1948-7193
DOIs
Publication statusPublished - Apr 2022

Keywords

  • 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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