Network Pharmacology and Computational Approach to Unveiling the Mechanism of Berberine in Depression

Depression is a prevalent and often underdiagnosed neuropsychiatric disorder. Natural herbal medicinal products are receiving more attention as potential antidepressants due to their efficacy and low side effects. Berberine, as a primary ingredient in the Indian medicinal plant Berberis vulgaris, has been shown to possess a promising antidepressant effect, although the mechanism of action remains unclear.

To elucidate the multifaceted mechanism of berberine in depression, an integrated computational approach combining network pharmacology, molecular docking, gene ontology (GO) analysis, and molecular dynamics (MD) simulation was employed. The interaction between berberine and potential protein targets was evaluated through molecular docking and binding affinity analyses.

The network analysis has identified the neuroactive ligand-receptor interaction-signalling pathway as the primary target, showing the highest binding affinity for the AKT Serine/Threonine Kinase 1 (AKT1) protein. The molecular docking predicts that AKT1 (-10.3 kcal/mol), HSP90AA1 (-8.8 kcal/mol), and STAT3 (-7.5 kcal/mol) may have the most significant binding affinity for berberine. MD simulations confirmed the stability of berberine within the inhibitor binding pockets of these proteins, primarily through hydrogen bonding and π-alkyl interactions.

Berberine's antidepressant effects appear to be caused by a synergistic, polypharmacological mechanism. It may influence a network of proteins involved in depression's pathophysiology, including AKT1 for cell survival and synaptic plasticity, STAT3 for neuroinflammation, and HSP90AA1 as a master regulator.

The study suggests that berberine may alleviate depression through a multi-target mechanism, potentially by modulating the AKT1 signalling pathway along with other key targets like STAT3 and HSP90AA1. These predictive results suggest that berberine is a compelling candidate that could be useful for further investigation in both in vitro and in vivo studies, with the potential aim of treating psychiatric-related depression disorder as a potential therapeutic or adjunctive agent for depression.