Affinities of Selective-Serotonin Reuptake Inhibitor (SSRI) for Human Transporters: Molecular Modeling and Quantum Chemical Studies

Abstract

SSRIs are the most commonly prescribed medication to treat mood, anxiety and personality disorders. SSRIs relieve symptoms of depression by selectively inhibiting the reuptake of the neurotransmitter serotonin from the synaptic cleft by the human serotonin transporter (hSERT). However, SSRIs also have weak affinities for the homologs of hSERT, the dopamine and norepinephrine transporters (hDAT and hNET). These promiscuous interactions of SSRIs with other neurotransmitter transporters can lead to severe side effects. A thorough understanding of the structural basis of SSRI-transporter interaction and selectivity is thus imperative for developing more potent and specific depression medication. In this study, we constructed homology models of hSERT, hDAT and hNET bound to the SSRIs, namely, sertraline, R-flouxetine and S-fluoxetine. Five models were selected for each complex and protein residues within 3.5 Ǻ of the bound SSRI were designated as the drug-binding residues. A total of 45 high-level quantum chemical calculations were performed using dispersion-corrected density functional theory (DFT-D3) and Ahlrich's triple-zeta basis set to estimate the interaction energies between drug-binding residues and SSRIs. Analysis of interaction energies clearly showed that hSERT exhibits the most favorable interaction energy for all three SSRIs. Analysis of non-covalent interactions between the protein and the inhibitors revealed the presence of additional stabilizing interactions in hSERT-SSRI complexes. Residues at structurally-equivalent positions in hNET and hDAT clearly lack those favorable interactions. These calculations, for the first time, shed light on specific interactions responsible for SSRI selectivity in human neurotransmitter transporters. This knowledge can help in rational design of highly selective and more potent antidepressants.