Prediction of the therapeutic mechanism of Sugemule-4 in insomnia treatment using network pharmacology and molecular docking

This study aimed to identify the active components and related target pathways as well as examine the potential mechanisms of action of Sugemule-4 (SGML-4) for the treatment of insomnia, based on network pharmacology, molecular docking analysis, and molecular dynamics simulation. The active compounds of SGML-4 were retrieved from the Traditional Chinese Medicine Systems Pharmacology, Herbal Medicine Resource, and Encyclopedia of Traditional Chinese Medicine databases. Their potential targets were predicted using the SwissTargetPrediction platform, while known insomnia-related targets were gathered from GeneCards, Online Mendelian Inheritance in Man, Therapeutic Target Database, Drugbank, and PharmGKB. The intersection of compound-related targets was then determined. Next, a protein-protein interaction network was constructed and visualized using the STRING online platform and Cytoscape 3.10.3 software. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were conducted using the DAVID platform. Based on these analyses, key targets and the principal active compounds of Sugemule IV were selected for molecular docking studies using AutoDock software to evaluate their potential interactions. Finally, molecular dynamics simulations were conducted using GROMACS software to assess the stability of the protein-compound complexes. A total of 106 active compounds and 364 overlapping targets were identified. Luteolin, pinocembrin, piplartine, lysicamine, and apigenin showed the highest degree values, and AKT1, glyceraldehyde-3-phosphate dehydrogenase, tumor necrosis factor, albumin, and epidermal growth factor receptor (EGFR) were identified as core targets. Gene Ontology analysis indicated enrichment in chemical synaptic transmission and G protein-coupled receptor signaling. Kyoto Encyclopedia of Genes and Genomes analysis revealed serotonergic synapse and calcium signaling as major pathways. Molecular docking showed strong binding affinities between active compounds and targets, particularly EGFR, which formed stable hydrogen bonds. Molecular dynamics confirmed stable interactions of EGFR with apigenin, luteolin, and piplartine. SGML-4 exerts anti-insomnia effects through multi-target and multi-pathway mechanisms. Apigenin, luteolin, and piplartine are the core active components, and EGFR is identified as the central target, potentially acting through serotonergic synapses and calcium signaling pathways.