Homology Modeling of the Serotonin Transporter: Insights into the Primary Escitalopram-binding Site

The serotonin transporter (SERT) is one of the neurotransmitter transporters that plays a critical role in the regulation of endogenous amine concentrations and therefore is an important target for therapeutic agents affecting the central nervous system. The recently published, high resolution X‐ray structure of the closely related amino acid transporter, Aquifex aeolicus leucine transporter (LeuT), provides an opportunity to develop a three‐dimensional model of the structure of SERT. We present herein a homology model of SERT using LeuT as the template and containing escitalopram as a bound ligand. Our model explains selectivities known from mutational studies and varying ligand data, which are discussed and illustrated in the paper. Insights into the serotonin transporter–escitalopram complex. A three‐dimensional molecular model for the serotonin transporter in complex with the allosteric serotonin reuptake inhibitor escitalopram was constructed. The model explains various protein–ligand interactions in the high‐affinity ligand‐binding site.