Modeling the Binding of Five Selective Serotonin Reuptake Inhibitors (SSRIs) to the Human Serotonin Transporter (hSERT) to Allosteric and Central Binding Sites

Modeling the Binding of Five Selective Serotonin Reuptake Inhibitors (SSRIs) to the Human Serotonin Transporter (hSERT) to Allosteric and Central Binding Sites

Alvin Sherman Library

Rates of depression are rising globally. A proposed physiological basis of depression is low levels of neurotransmitters, in particular serotonin. SSRIs are a form of medication that is used to treat depression disorders by inhibiting the reuptake of serotonin by Human Serotonin transporter (hSERT). Modeling the structure of hSERT allows for rational drug design, potentially improving the medications that are available to the public. The Protein Data Bank file of hSERT was retrieved (PDB ID: 5I6Z). Additional PDB files were utilized to analyze various SSRIs and their respective central and allosteric binding sites to determine the most critical portions required for effective SSRI binding. A three-dimensional molecular model was developed from the PDB files by examining the binding of 5 SSRIs at the allosteric and central binding site of hSERT, as found in the 7 PDBs listed above using the protein visualization program iCn3D. Through reviewing the annotated amino sequence provided in iCn3D for each supplemental PDB, a comprehensive list of amino acids participating in central and/or allosteric binding was created, which was used to develop the ‘heat map’ represented in the three-dimensional model. Based on reported structure-activity relationship analysis, a novel molecular inhibitor, “ParoFluoxetine”, was developed. After trying various combinations of SSRIs, “Paro-Fluoxetine” had the highest binding affinity out of all combinations (–8.294 kJ/mol). Developing a novel drug molecule that targets the human serotonin transporter and modeling the drug-receptor interaction provides opportunities to create drug treatments with enhanced therapeutic efficiency to better treat major depressive disorder.