Avaliação in silico das interações do transportador de serotonina com fármacos antidepressivos e ácido alfa-lipóico

Abstract

Depression is a highly prevalent mood disorder, affecting more than 300 million people worldwide and standing as the leading cause of global disability. Among pharmacological approaches, the serotonin transporter (SLC6A4), also known as SERT or 5-HTT, plays a central role by promoting the reuptake of serotonin released into the synaptic cleft, making it a prominent therapeutic target of most currently available antidepressants. Despite the effectiveness of these medications, clinical response is frequently limited due to delayed onset of action and the occurrence of partial or even null responses in many cases, highlighting the need for new therapeutic strategies. In this context, alpha-lipoic acid (LPA), recognized for its antioxidant and anti-inflammatory properties, has emerged as a modulator of systems involved in depression. The aim of this study was to investigate, using computational techniques, the interaction of LPA with SERT’s orthosteric site (S1), comparing its performance to classic ligands such as serotonin, paroxetine, and desvenlafaxine, with the intention of exploring possible alternative mechanisms of antidepressant action. To this end, a model of human SERT was built using homology modeling and ab initio modeling. The ligands had their structures optimized and underwent molecular docking studies to evaluate their binding modes at the transporter’s binding sites. Next, molecular dynamics simulations were performed to analyze the stability of the formed complexes, and binding free energies were calculated using the MM/PBSA method. The results showed that while paroxetine displayed higher affinity for SERT’s S1 site, LPA did not act as a direct competitive inhibitor at this location. The analyses indicate that the antidepressant effects observed for LPA may be related to indirect mechanisms, such as modulation of neuroinflammation and oxidative stress, reinforcing its potential as an adjuvant agent in integrated pharmacological strategies and in drug repurposing.