title: Binding of the multimodal antidepressant drug vortioxetine to the human serotonin transporter.
abstract: Selective inhibitors of the human serotonin transporter (hSERT) have been first-line treatment against depression for several decades. Recently, vortioxetine was approved as a new therapeutic option for the treatment of depression. Vortioxetine represents a new class of antidepressant drugs with a multimodal pharmacological profile that in addition to potent inhibition of hSERT include agonistic or antagonistic effects at different serotonin receptors. We used a combination of computational, chemical, and biological methods to decipher the molecular basis for high affinity binding of vortioxetine in hSERT. X-ray crystal structures of the bacterial amino acid transporter LeuT and the Drosophila melanogaster dopamine transporter were used to build homology models of hSERT. Comparative modeling and ligand docking suggest that vortioxetine can adopt several distinct binding modes within the central binding site of hSERT. To distinguish between the identified binding modes, we determined the effect of 57 functional hSERT point mutants on vortioxetine potency and characterized seven structurally related analogs of vortioxetine in a subset of the point mutants. This allowed us to determine the orientation of vortioxetine within the central binding site and showed that only one of the proposed binding modes is functionally relevant. The findings provide important new insight about the molecular basis for high affinity recognition of vortioxetine in hSERT, which is essential for future structure-based drug discovery of novel multimodal drugs with fine-tuned selectivity across different transporter and receptor proteins in the human brain.
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen , Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Jacob
authors.initials: J
authors.lastname: Andersen
authors.affiliation: Center for Insoluble Protein Structures (inSPIN) and Interdisciplinary Nanoscience Center (iNANO), Department of Chemistry, Aarhus University , Langelandsgade 140, DK-8000 Aarhus C, Denmark.
authors.forename: Lucy Kate
authors.initials: LK
authors.lastname: Ladefoged
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen , Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Danyang
authors.initials: D
authors.lastname: Wang
authors.affiliation: Center for Insoluble Protein Structures (inSPIN) and Interdisciplinary Nanoscience Center (iNANO), Department of Chemistry, Aarhus University , Langelandsgade 140, DK-8000 Aarhus C, Denmark.
authors.forename: Trine N Bjerre
authors.initials: TN
authors.lastname: Kristensen
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen , Universitetsparken 2, DK-2100 Copenhagen, Denmark.|Lundbeck Research Denmark , H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark.
authors.forename: Benny
authors.initials: B
authors.lastname: Bang-Andersen
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen , Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Anders S
authors.initials: AS
authors.lastname: Kristensen
authors.affiliation: Center for Insoluble Protein Structures (inSPIN) and Interdisciplinary Nanoscience Center (iNANO), Department of Chemistry, Aarhus University , Langelandsgade 140, DK-8000 Aarhus C, Denmark.
authors.forename: Birgit
authors.initials: B
authors.lastname: Schiøtt
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen , Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Kristian
authors.initials: K
authors.lastname: Strømgaard
mesh_terms: D000928:Antidepressive Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D017354:Point Mutation; D011485:Protein Binding; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000737:chemistry / Q000494:pharmacology*; D000078784:Vortioxetine
chemical_list: D000928:Antidepressive Agents; D010879:Piperazines; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D013440:Sulfides; D000078784:Vortioxetine
keywords: antidepressant drug; induced fit docking; neurotransmitter transport; pharmacology; serotonin transporter; structure-based drug design