Files
Submission Date
2024
Abstract
A staggering 21 million people are currently affected by Major Depressive Disorder (MDD), a condition that can impact an individual’s ability to complete even the most basic everyday activities. Serotonin is a neurotransmitter which is taken back to nerve cells through a process called reuptake. However, Selective Serotonin Reuptake Inhibitor, (SSRIs), block this process, therefore making more serotonin available to help promote communication in the brain.
The Protein Data Bank file of ts2 human serotonin transporter was retrieved from the Protein Data Bank (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. These PDB files include 5I71 (only S-citalopram at the central site with nothing bound at allosteric site), 5I6X (paroxetine at the central binding site, nothing at allosteric binding site), 5I74 (Br-citalopram at the central site, with nothing at the allosteric binding site), 5I73 (S-Citalopram central and allosteric ), 5I75 (S-Citalopram central and Br-Citalopram at the allosteric binding site), 6AWO (Sertraline at the central site, nothing at the allosteric binding site) and 6AWP (Fluvoxamine at central site, nothing at the allosteric binding site).
A 3-D molecular model was developed from the PDB files by examining binding of 5 of these SSRIs (Br-citalopram, S-Citalopram, Sertraline, and fluvoxamine) at both the allosteric and central binding site of hSERT as found in the 7 PDBs listed above using iCn3D. ICn3D is a web-based 3D structure viewer that showcases three dimensional biological molecules and chemicals. The alpha helices important in serotonin transport within the serotonin transport protein are noted: helices 1A, 1B are light pink and 6A, 6B are lavender. A heat map was generated to demonstrate the prevalence of the amino acids that were essential in central and allosteric binding. Specifically, the heat map of amino acid participation across the 7 PDBs that had drug binding to the central site, with the darkest blue indicating that the amino acid participates in drug binding in the central site in 7 of 7 PDBs, ranging to a muted orange indicating that there was drug binding in in 1 of 7 the 7 PDBs. Furthermore, the amino acids participating in 1 out of the 2 allosteric bind sites are indicated in lime green while amino acids that are involved in both sites are indicated in teal. Based on the SSRIs tested in this experiment, the inhibitor Paroxetine had the highest binding affinity of –7.647 kJ/mol. Based on reported structure-activity relationship analysis, a novel molecular inhibitor, “Paro-Fluoxetine”, was developed. After comparing various combinations between functional groups of the four SSRIs: Fluoxetine, Sertraline, Escitalopram and Paroxetine, it was concluded that the R1 group of Paroxetine, R2 group of Fluoxetine and the R3 group of Fluoxetine had the highest biding affinity out of all combinations tested, that being –8.294 kJ/mol. It is plausible that the functional groups of Fluoxetine primarily are responsible for increased binding affinity.
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 MDD.
Recommended Citation
Alvarez Coke, Alessandra; Mathew, Ivanna; Saai Talanki, Srika; Schmitt Lavin, Emily F.; and Sikora, Arthur, "Modeling the Binding of Five Selective Serotonin Reuptake Inhibitors (SSRIs) to the Human Serotonin Transporter (hSERT) to Allosteric and Central Binding Sites" (2024). Protein Modeling Reports. 20.
https://nsuworks.nova.edu/protein_modeling_reports/20
Final Presentation for the course
Final Poster - Group 4.pdf (429 kB)
Poster regarding this research