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

G-protein coupled receptors (GPCRs) are importantpharmacological targets. Despitesubstantial progress, importantquestions still remain concerning the details of activation: how can aligand act as an agonist in one receptor but as an antagonist in ahomologous receptor, and how can agonists activate a receptor despitelacking polar functional groups able to interact with helix 5 as is thecase for the related adrenergic receptors? Studying vortioxetine (VXT),an important multimodal antidepressant drug, may elucidate bothquestions. Herein, we present a thorough in silico analysis of VXTbinding to 5-HT1A, 5-HT1B, and 5-HT7receptors and compare it withavailable experimental data. We are able to rationalize the differentialmode of action of VXT at different receptors, but also, in the case ofthe 5-HT1Areceptor, we observe the initial steps of activation thatinform about an activation mechanism that does not involve polar interaction with helix 5. The results extend our currentunderstanding of agonist and antagonist action at aminergic GPCRs.

Automated summary

Studying the action of multimodal antidepressant drug vortioxetine (VXT) on different receptors can provide insights into the mechanisms of agonist-antagonist dual behavior and activation without polar interaction with helix 5.