Flunarizine as a potential repurposed drug for the serotonin transporter inhibition: an integrated approach for therapeutic development against major depressive disorder.

Major depressive disorder (MDD) is a serious neuropsychiatric condition that affects millions of people worldwide, causing significant psychological distress and lifestyle deterioration. The serotonin transporter, which plays a critical role in regulating the uptake of serotonin (5-HT) back into presynaptic cells, is a primary target for antidepressants. Though selective serotonin reuptake inhibitors (SSRIs) are still the pharmacologic treatment of choice, alternative methods remain in demand to enhance the efficacy of treatment and offer more therapeutic options. Drug repurposing provides an efficient solution to speed up antidepressant research because it identifies existing FDA-approved medications that might inhibit the serotonin transporter. A virtual screening method was integrated into the study that examined 3620 FDA-approved drugs to discover new repurposed serotonin transporter-inhibiting molecules. The binding affinity, structural stability, and inhibitory potential were assessed using molecular docking and molecular dynamics (MD) simulations. Among the screened compounds, Flunarizine, a well-known calcium channel blocker, emerged as a promising serotonin transporter inhibitor due to its strong and stable binding configuration within the transporter's active site. Detailed molecular docking studies revealed that Flunarizine formed key interactions with critical residues of the serotonin transporter, suggesting its potential as an effective modulator. Subsequent 500-nanosecond MD simulations further confirmed the stability of the serotonin transporter-Flunarizine complex, demonstrating minimal structural deviations and maintaining crucial dynamic properties throughout the simulation trajectory. These findings highlight Flunarizine's potential for repurposing as a novel therapeutic agent targeting serotonin transport modulation. The study provides a solid foundation for further preclinical and clinical investigations into the antidepressant repurposing of Flunarizine.