%0 Journal Article %A Lucy Kate Ladefoged %A Rebekka Koch %A Philip C. Biggin %A Birgit Schiøtt %T Binding and activation of serotonergic G-protein coupled receptors by the multimodal antidepressant vortioxetine %D 2021 %R 10.1101/2021.01.05.425370 %J bioRxiv %P 2021.01.05.425370 %X G-protein coupled receptors 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? Studying vortioxetine, an important multimodal antidepressant drug, may elucidate both questions. Herein, we present a thorough in silico analysis of vortioxetine binding to 5-HT1A, 5-HT1B, and 5-HT7 receptors and compare to available experimental data. We are able to rationalize the differential mode of action of vortioxetine at different receptors, but also, in the case of the 5-HT1A receptor, we observe the initial steps of activation suggesting that interaction with helix 5 does not necessarily require a hydrogen bond as previously suggested. The results extend our current understanding of agonist and antagonist action at GPCRs.Competing Interest StatementThe authors have declared no competing interest. %U https://www.biorxiv.org/content/biorxiv/early/2021/01/06/2021.01.05.425370.full.pdf