IN SILICO IDENTIFICATION AND EVALUATION OF NOVEL PAROXETINE ANALOGUES AS POTENTIAL SEROTONIN TRANSPORTER (SERT) INHIBITORS

Abstract

Major depression, anxiety, and obsessive-compulsive disorder(OCD) are mental health problems that are linked to the poor work of the serotonin transporter (SERT). SERT is a protein that helps move serotonin (a brain chemical) back into nerve cells. This process is key for controlling how serotonin signals in the brain. When this system does not work well, it can cause unbalanced brain signals and lead to these conditions. Drugs called SSRIs, such as Paroxetine, are often used to block SERT and help fix these problems. However, these drugs can have side effects and may not help everyone. Because of this, new and better treatment options are needed. In this study, a computer-based method was used to find better SERT blockers that are similar in structure to Paroxetine. Using the SwissSimilarity tool, 327 similar compounds were found. These compounds were checked for how well they might work as drugs-like using SwissADME. This filter compounds Based on Molecular Charecterstics like lipophilicity,size, Hydrogen Bonding and blood-brain barrier. Out of these, 203 compounds with good drug-like traits were chosen for docking tests. The docking was done with AutoDock Vina on the PyRx platform. The 3D crystal structure of SERT (PDB ID: 5I6X) was prepared by removing water molecules and unnecessary chains. The binding site where Paroxetine fits was marked. The Docking results showed five similar compounds that had better binding strength than Paroxetine. showing stable interactions with Key amino acid residues such as TYR95, ASP98, ILE172, SER438, TYR176, and. Further ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) profiling using pkCSM identified three compounds (PubChem IDs: 11697676, 4470577, and 11100995) as non-mutagenic and pharmacokinetically favorable. These candidates demonstrated high gastrointestinal absorption, acceptable solubility, and compliance with Lipinski's Rule of Five. Overall, the study presents promising Paroxetine-like inhibitors with improved binding to SERT and better safety profiles. These findings support their potential development as new antidepressant agents, though additional laboratory validation in biological models is necessary to confirm their therapeutic effectiveness.