Elasbali Abdelbaset Mohamed, Ali Ahmed S, Mohammad Taj, Adnan Mohd, Shamsi Anas, Hassan Md Imtaiyaz
Department of Clinical Laboratory Science, College of Applied Medical Sciences-Qurayyat, Jouf University, Qurayyat, Saudi Arabia.
King Salman Center for Disability Research, Riyadh, Saudi Arabia.
Front Pharmacol. 2025 May 13;16:1599297. doi: 10.3389/fphar.2025.1599297. eCollection 2025.
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.
重度抑郁症（MDD）是一种严重的神经精神疾病，影响着全球数百万人，导致严重的心理困扰和生活方式恶化。血清素转运体在调节血清素（5-HT）重新摄取到突触前细胞中起着关键作用，是抗抑郁药的主要靶点。尽管选择性5-羟色胺再摄取抑制剂（SSRIs）仍然是首选的药物治疗方法，但仍需要其他方法来提高治疗效果并提供更多治疗选择。药物重新利用提供了一种有效的解决方案，以加速抗抑郁药的研究，因为它可以识别现有的FDA批准的可能抑制血清素转运体的药物。本研究采用虚拟筛选方法，对3620种FDA批准的药物进行了研究，以发现新的具有血清素转运体抑制作用的药物。使用分子对接和分子动力学（MD）模拟评估结合亲和力、结构稳定性和抑制潜力。在筛选出的化合物中，氟桂利嗪是一种著名的钙通道阻滞剂，由于其在转运体活性位点内具有强大而稳定的结合构型，成为一种有前景的血清素转运体抑制剂。详细的分子对接研究表明，氟桂利嗪与血清素转运体的关键残基形成了关键相互作用，表明其作为一种有效调节剂的潜力。随后的500纳秒MD模拟进一步证实了血清素转运体-氟桂利嗪复合物的稳定性，在整个模拟轨迹中显示出最小的结构偏差并保持关键的动力学特性。这些发现突出了氟桂利嗪作为一种靶向血清素转运调节的新型治疗药物重新利用的潜力。该研究为进一步对氟桂利嗪的抗抑郁药重新利用进行临床前和临床研究提供了坚实的基础。
