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

TY - JOUR

T1 - Binding and Activation of Serotonergic G-Protein Coupled Receptors by the Multimodal Antidepressant Vortioxetine

AU - Ladefoged, Lucy Kate

AU - Koch, Rebekka

AU - Biggin, Philip C.

AU - Schiøtt, Birgit

N1 - Publisher Copyright: © 2022 by the authors.

PY - 2022/4

Y1 - 2022/4

N2 - 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.

AB - 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.

KW - 5-HT

KW - GPCR

KW - serotonin

KW - vortioxetine

KW - STRUCTURAL INSIGHTS

KW - CRYSTAL-STRUCTURE

KW - PARAMETERS

KW - PREDICTION

KW - 5-HT7

KW - TOLERABILITY

KW - 5-HT1A

KW - DYNAMICS

KW - 5-HT1B

KW - COUPLED RECEPTORS

KW - FORCE-FIELD

KW - LIGAND

KW - TOOL

KW - Piperazines/pharmacology

KW - Vortioxetine/pharmacology

KW - Receptors, G-Protein-Coupled

KW - Antidepressive Agents/pharmacology

KW - Serotonin/metabolism

UR - http://www.scopus.com/inward/record.url?scp=85127869497&partnerID=8YFLogxK

U2 - 10.1021/acschemneuro.1c00029

DO - 10.1021/acschemneuro.1c00029

M3 - Journal article

C2 - 35348335

AN - SCOPUS:85127869497

SN - 1948-7193

VL - 13

SP - 1129

EP - 1142

JO - ACS Chemical Neuroscience

JF - ACS Chemical Neuroscience

IS - 8

ER -