Pakistan Journal of Pharmaceutical Sciences

Abstract: Background: Chronic insomnia impairs health-related quality of life and current pharmacotherapies carry substantial adverse-effect profiles, prompting the search for safer multi-target interventions. Kong Sheng Pillow Zhongdan (KSPZ), a classical herbal formula, is empirically used for sleep disturbance, yet its molecular basis remains unclear. Objectives: To elucidate the putative mechanisms of KSPZ against chronic insomnia through a network-pharmacology approach and to prioritise targets for experimental validation. Methods: Active compounds were retrieved from TCMSP, HIT2.0 and TCMIP and filtered by oral bioavailability ?30% and blood–brain barrier permeability ?–0.3. Insomnia-related genes were collected from DisGeNET, GeneCards and OMIM. Overlapping targets defined the “core prescription–insomnia” interactome (126 genes). Protein–protein interaction networks were constructed with STRING and hub nodes identified by CytoHubba. GO, KEGG and Reactome enrichment analyses were performed with clusterProfiler; key ligand–target pairs were evaluated by AutoDock Vina. A drug–ingredient–target–disease network was visualised in Cytoscape. Results: Twenty-eight bioactive compounds (e.g., quercetin, kaempferol, luteolin) were mapped to 126 shared targets enriched in neuro-inflammation (IL-17, TNF, NF-?B), serotonergic and dopaminergic synapses, circadian rhythm and cAMP signalling. Top hub genes included TNF, IL6, AKT1, PTGS2, BDNF and DRD2. Molecular docking showed high affinities (?G ? –8.5 kcal mol-¹) for quercetin–GABRA1, kaempferol–HTR2A and luteolin–BDNF complexes, supporting modulatory effects on inhibitory/excitatory neurotransmission and neuroplasticity. Conclusion: KSPZ exerts multi-level effects on neuro-immune regulation, inflammation and circadian pathways, providing a rational basis for its empirical use in chronic insomnia. In-vivo validation of the predicted neurotransmitter and cytokine targets is warranted to translate these network findings into clinical applications.