The antidepressant drug vilazodone is an allosteric inhibitor of the serotonin transporter

Per Plenge,Louise Laursen,Iris E Kalenderoglou,Kristine Salomon,Dongxue Yang,Jonathan A Coleman,Eric Gouaux,Amy H Newman,Claus J Loland

doi:10.1038/s41467-021-25363-3

Abstract

Depression is a common mental disorder. The standard medical treatment is the selective serotonin reuptake inhibitors (SSRIs). All characterized SSRIs are competitive inhibitors of the serotonin transporter (SERT). A non-competitive inhibitor may produce a more favorable therapeutic profile. Vilazodone is an antidepressant with limited information on its molecular interactions with SERT. Here we use molecular pharmacology and cryo-EM structural elucidation to characterize vilazodone binding to SERT. We find that it exhibits non-competitive inhibition of serotonin uptake and impedes dissociation of [3H]imipramine at low nanomolar concentrations. Our SERT structure with bound imipramine and vilazodone reveals a unique binding pocket for vilazodone, expanding the boundaries of the extracellular vestibule. Characterization of the binding site is substantiated with molecular dynamics simulations and systematic mutagenesis of interacting residues resulting in decreased vilazodone binding to the allosteric site. Our findings underline the versatility of SERT allosteric ligands and describe the unique binding characteristics of vilazodone.

Highlights

COS-7 cells were transiently transfected with serotonin transporter (SERT) WT and preincubated with increasing concentrations of VLZ to obtain binding equilibrium before adding [3H]5-HT (Fig. 1a)
All antidepressant drugs targeting SERT have been reported to bind with high affinity to the orthosteric, central binding site
We report that VLZ binds with high affinity to the S2 site located to the SERT extracellular vestibule

Summary

Introduction

All characterized SSRIs are competitive inhibitors of the serotonin transporter (SERT). We use molecular pharmacology and cryo-EM structural elucidation to characterize vilazodone binding to SERT. We find that it exhibits non-competitive inhibition of serotonin uptake and impedes dissociation of [3H]imipramine at low nanomolar concentrations. Selective serotonin reuptake inhibitors (SSRIs) were developed to bind SERT with high affinity and specificity, resulting in better tolerance and fewer side effects[28,29]. We have reported on the first small-molecule inhibitor possessing high affinity to the S2 site, Lu AF60097 (Supplementary Fig. 1), that inhibits 5-HT transport by SERT via a mixed competitive and non-competitive mechanism, suggesting it binds both the allosteric and central sites[40]. The allosteric interaction has a synergistic effect, which could alleviate side effects from IMI treatment while preserving its therapeutic effects

Methods

Results

Conclusion