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.

Modeling and Mutational Analysis of the Binding Mode for the Multimodal Antidepressant Drug Vortioxetine to the Human 5-HT3A Receptor

“…The antidepressant effect of vortioxetine involves its highly potent inhibition of the serotonin transporter (Andersen et al, 2009;Bang-Andersen et al, 2011). We have previously reported a model of vortioxetine bound in a human serotonin transporter (hSERT) (Andersen et al, 2015). Key insights into the role of functional groups of vortioxetine in binding hSERT and h5-HT 3A are of potential interest for future drug design of multimodal drugs targeting these serotonergic proteins.…”

“…A contrasting feature is the overall role of the two phenyl rings of vortioxetine for binding at hSERT and h5-HT 3A . At h5-HT 3A , the phenyl rings make several p/p and cation/p interactions, in particular to residues in the aromatic box, whereas in hSERT hydrophobicity of the phenyl rings rather than aromaticity is most important for binding (Andersen et al, 2015).…”

“…Ligand Preparation. The structure of granisetron was extracted from the crystal structure of 5-HTBP (Protein Data Bank ID: 2YME), while the structure of vortioxetine was prepared as described in Andersen et al (2015). Following assignment of bond orders and atom types in Maestro 10.1 (Schrödinger Suite 2015) (Schrodinger LLC, New York, NY), the granisetron structure was minimized and then subjected to a conformational search using the mixed torsional/lowmode sampling method, the optimized potentials for liquid simulations 2.1 force field, and an implicit water model in MacroModel 10.7 (Schrodinger Suite 2015).…”

SLC transporters: structure, function, and drug discovery

“…This method has been employed in combination with mutagenesis experiments, to propose a unique binding mode of the anti-depressant drug Vortioxetine in homology models of the human serotonin transporter (SLC6A4/SERT). 80 …”

Genetically encoded photocrosslinkers locate the high-affinity binding site of antidepressant drugs in the human serotonin transporter

“…Due to a better incorporation tolerance and generally higher activities of azF mutants compared with BzF mutants, we chose to focus on azF mutants. We selected five mutants surrounding the S1-binding site (Y95azF, I168azF, Y175azF, F335azF and F341azF) and five mutants surrounding the S2-binding site (W103azF, Y107azF, W182azF, Y487azF and K490azF), based on spatial orientation and distance from the proposed binding sites in a homology model of hSERT 42 ( Fig. 2a ).…”