Molecular Docking Study of Bioactive Compounds from Averrhoa bilimbi L. Targeting the Serotonin Transporter (SERT) as Potential Therapeutic Candidates for Phobic Disorders

Abstract

Introduction— Social anxiety disorder and phobic conditions are associated with dysregulation of serotonergic neurotransmission, in which serotonin transporter (SERT) plays a key role in serotonin reuptake at the presynaptic membrane. SERT is a molecular target for selective serotonin reuptake inhibitors (SSRIs), making it a target for the identification of inhibitors from natural products using computational approaches.

Methods — Twenty-two compounds retrieved from the KNApSAcK database were screened using PASS Online. Drug-likeness was evaluated based on Lipinski's Rule of Five. Molecular docking against SERT was performed to determine binding affinity, RMSD, and ligand–protein interactions using paroxetine as the reference ligand. ADMET analysis was conducted to predict pharmacokinetic and toxicity properties.

Results — PASS screening identified 15 compounds with higher probability of activity than inactivity, with tetradecylamine exhibiting the highest Pa value (0.939). Molecular docking showed that anapheline had the strongest binding affinity among the tested compounds (−7.1 kcal/mol), whereas paroxetine exhibited the lowest binding energy (−8.7 kcal/mol). Key interacting residues included TYR95, ILE172, PHE335, VAL501, ASP98, and GLU494. ADMET prediction indicated high intestinal absorption (85.76–94.93%), favorable blood–brain barrier permeability, and low predicted toxicity for most compounds.

Conclusion — Bioactive compounds from Averrhoa bilimbi L. demonstrated potential inhibitory activity against SERT based on integrated in silico analyses. Among the evaluated compounds, anapheline emerged as the most promising candidate because of its favorable binding affinity and pharmacokinetic profile, warranting further experimental validation.