Potential Anti-inflammatory Properties of Corydalis rhizoma for Co-Treatment of Neuropathic Pain and Major Depressive Disorder: Network Pharmacology with Molecular Docking and Molecular Dynamics Simulation Approaches

Background: Neuropathic pain (NP) frequently coexists with major depressive disorder (MDD), sharing common molecular pathways that affect brain function. Targeting these molecular pathways through multi-target herbal remedies, such as the extract from Corydalis rhizoma (CR), may offer new therapeutic strategies; however, the variability in composition and potential toxicity of natural products, as seen with mishandled herbs, presents significant challenges in the U.S. herbal medicine landscape. Objective: This study utilized network pharmacology and molecular docking to explore the mechanisms linking NP and MDD via the herbal remedy CR, while addressing the challenges posed by natural product variability and potential toxicity. Methods: We identified potential bioactive components of CR using various databases and assessed their pharmacological properties and toxicity. Common targets of CR's bioactive components for treating MDD/NP were identified, followed by protein-protein interaction (PPI) analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to select potential pathways. Additionally, docking analyses evaluated the binding affinity between ligands and receptors, while molecular dynamics (MD) simulations were conducted to assess the stability and interactions of these complexes over time. Results: We identified 24 active ingredients in CR, primarily alkaloids and phytosterols, with favorable pharmacokinetics, including the ability to cross the blood-brain barrier and low toxicity at lower doses. These ingredients were associated with 125 genes and five key therapeutic targets— AKT1, CASP3, ESR1, BCL2, and MAPK3—integral to synaptic signaling and neurotransmitter activity. The molecular docking analysis revealed significant interactions, with CASP3 and tetrahydrocorysamine demonstrating the highest binding affinity at −9.6 kcal/mol, suggesting their potential for neuroprotection, antidepressant effects, and pain relief. MD simulations confirmed the strong binding affinity predicted by docking, particularly for the CASP3- THC complex. Conclusion: This study highlights the therapeutic potential of CR's active components in treating MDD/NP through a comprehensive framework of network pharmacology, molecular docking, and MD simulations. While the findings are promising, further preclinical research is necessary to validate the safety, efficacy, and mechanisms of action of these compounds.