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J Chem Inf Model. 2011 Sep 26;51(9):2417-26. doi: 10.1021/ci200280m. Epub 2011 Sep 2.

Discovery of novel selective serotonin reuptake inhibitors through development of a protein-based pharmacophore.

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  • 1Department of Chemistry and Biochemistry and Center for Computational Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, United States.


The serotonin transporter (SERT), a member of the neurotransmitter sodium symporter (NSS) family, is responsible for the reuptake of serotonin from the synaptic cleft to maintain neurotransmitter homeostasis. SERT is established as an important target in the treatment of anxiety and depression. Because a high-resolution crystal structure is not available, a computational model of SERT was built based upon the X-ray coordinates of the leucine transporter LeuT, a bacterial NSS homologue. The model was used to develop the first SERT structure-based pharmacophore. Virtual screening (VS) of a small molecule structural library using the generated SERT computational model yielded candidate ligands of diverse scaffolds. Pharmacological analysis of the VS hits identified two SERT-selective compounds, potential lead compounds for further SERT-related medication development.

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