The monoamine transport proteins (MATs), which include the serotonin, dopamine, and norepinephrine transporters (SERT, DAT, and NET), are implicated in the treatment of many neuropsychological disorders (depression, anxiety, post-traumatic stress disorder (PTSD)) and are targets of widely abused drugs (cocaine and amphetamine). The MATs are composed of 12 transmembrane domains with the primary binding pocket (S1) positioned within the central core. Transport occurs through an alternating access mechanism in which the ligand, coupled with sodium and chloride ions, binds to an outward-facing SERT conformation (extracellularly open) and triggers the transition to an inward-facing conformation (intracellularly open) before releasing the substrates. Treatment of depression has been focused on modulating serotonin signaling through the inhibition of SERT with the selective serotonin reuptake inhibitors (SSRIs), the major class of antidepressants that stabilize the outward-facing conformation of SERT. Prior efforts to use structure-based drug design to study SERT have relied on homology modeling using a bacterial leucine transporter or the <i>drosophila</i> DAT as structural templates. Recent elucidation of the human SERT crystal structures (PDB ids. 5I6X, 5I71, 5I73, 6AWN, 6AWO) with antidepressants bound to the S1 pocket provide a unique opportunity to apply rational drug design methods to evaluate potential inhibitors of SERT. For this study, the SERT protein (PDB id. 5I71, 3.15 Å resolution) was structurally mutated back to the wild-type amino acid sequence using the Molecular Operating Environment (MOE) software, and computationally relaxed the structure through molecular dynamics simulations using ACEMD software. Currently, a library of fragment-like compounds is being virtually screened within the S1 binding pocket using Autodock4 software. It is expected that the results will provide lead compounds that will be pharmacologically evaluated to identify new inhibitors of SERT.

<i>In silico</i> fragment screening of the human serotonin transporter

256th National Meeting (2018)

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In silico fragment screening of the human serotonin transporter