Abnormalities in serotonin levels can lead to depression and anxiety, as well as other mental disorders such as obsessive compulsive disorder. The serotonin transporter (SERT) plays a key role in the regulation of synaptic serotonin (5-hydroxtryptamine, 5-HT) levels and therefore is the major target for antidepressants including both the tricyclic antidepressants and selective serotonin reuptake inhibitors. The antidepressants affect the concentration of the serotonin by inhibiting the reuptake of the 5-HT into nerve cells. To examine the molecular mechanism of their different binding affinities the interactions between ligands and serotonin transporter were studied.

In the present study molecular modelling techniques were used to study the interaction between ligands and SERT. The SERT model was based on the crystal structure of the bacterial homologue Na⁺/Cl^- dependent neurotransmitter transporters from Aquifex aeolicus (LeuT_Aa) [1-3]. For the docking studies two sets of ligands were considered: ligands with quite high affinity, and ligands with a nitro group at the quinoline moiety with much lower affinity for SERT. The ligands were docked to the SERT model using the ICM (Internal Coordinate Mechanics) molecular modelling software.

The docking studies indicate that the binding site of the SERT model constituted amino acids in transmembrane helices (TMHs): 1, 3, 6, 8 for all the studied ligands. The ligands without a nitro group at the quinoline moiety interacted also with amino acids in TMH 10. In complexes of SERT and the ligands with the nitro group at the quinoline moiety a steric interactions between ligand and transporter protein were observed.

Additionally, a putative substrate binding site corresponding to low affinity binding was identified in the pore formed between TMHs 1, 6, 10 and 11. The docking of ligands to this binding site pinpointed an additional region that might be considered for development of new inhibitors.

Acknowledgement
This study was partly supported by the Research Network coordinated by Insititute of Organic Chemistry Polish Academy of Sciences

References

[1] Yamashita A., Singh S.K., Kawate T., Jin Y., Gouaux E. Crystal structure of a bacterial homologoue of Na⁺/Cl^- dependent neurotransmitter transporters. Nature, 2005;437:21-29.

[2] Ravna A.W., Jaronczyk M. and Sylte I. A homology model of SERT based on the LeuT_Aa template. Bioorganic & Medicinal Chemistry Letters, 2006;16:5594-5597.

[3] Jarończyk M., Chilmonczyk Z., Mazurek A.P., Nowak G., Ravna A.W., Kristiansen K., Sylte I., The molecular interactions of buspirone analogous with the serotonin transporter, Biochemical Pharmacology, submitted.

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