In-Silico Drug Discovery of Flavonoids Targeting the Human Serotonin Transporter: A Multi-Approach Computational Study for Depression

Background: Depression is a prevalent neuropsychiatric disorder characterized by serotonin (5-HT) deficiency, with the human serotonin transporter (hSERT) serving as a critical target for therapeutic intervention. Although selective serotonin reuptake inhibitors (SSRIs) are widely prescribed, their clinical efficacy is often limited by adverse effects and treatment resistance. Flavonoids, a class of naturally occurring polyphenolic compounds, have demonstrated potential in modulating hSERT activity. This study employs a multi-faceted computational drug discovery approach to identify flavonoid-based hSERT inhibitors with enhanced binding affinity, pharmacokinetics, and stability. A comprehensive in-silico framework, incorporating molecular docking (Glide XP), ADMET profiling, MM-GBSA free energy calculations, and molecular dynamics (MD) simulations, was utilized to screen and evaluate flavonoid candidates as prospective antidepressant agents. Results: Molecular docking analyses identified Globularicitrin as the most potent hSERT binder, exhibiting a docking score of -15.357, surpassing Fluoxetine (-10.306). ADMET predictions indicated optimal pharmacokinetic properties with a high probability (94-100%) of oral absorption. MM-GBSA calculations confirmed the stability of the Globularicitrin-hSERT complex, with a ΔG Bind of -23.16 kcal/mol. MD simulations conducted over a 100-ns trajectory demonstrated stable RMSD values (2.0–2.4 Å) and sustained protein-ligand interactions, with ASP-98 (90% occupancy), ARG-104 (94%), and TYR-95 (86%) forming persistent hydrogen bonds within the binding pocket, further corroborating its structural stability. Conclusions: The computational findings indicate that Globularicitrin exhibits superior hSERT binding affinity, favorable pharmacokinetics, and robust structural stability compared to Fluoxetine. These results suggest that Globularicitrin represents a promising candidate for alternative antidepressant development, warranting further experimental validation to assess its therapeutic efficacy in preclinical and clinical applications.