Multi-target anti-hangover mechanisms of andrographolide and its analogs: a hypothesis-generating in silico, in vitro...

An alcohol hangover is a pathophysiological condition caused by excessive ethanol intake, characterized by acetaldehyde accumulation, oxidative stress, neuroinflammation, and dysregulated neurotransmitter signaling. Despite its global socioeconomic impact, current interventions address symptoms rather than underlying biochemical disturbances. Andrographolide, a labdane diterpenoid from Andrographis paniculata, has antioxidant, anti-inflammatory, hepatoprotective, and neuroprotective properties, but its relevance to hangover mechanisms remains uninvestigated. This hypothesis-generating study assessed andrographolide and its analogs-andrographin, neoandrographolide, and 14-deoxy-11,12-didehydroandrographolide-11,12-dehydroandrographolide-using network pharmacology, molecular docking, and in vitro methods. Network pharmacology identified protein targets associated with hangover pathophysiology. Aldehyde dehydrogenase 2 (ALDH2) and GABA_A receptors were included for molecular docking due to their roles in acetaldehyde detoxification and alcohol-induced neurotransmitter imbalance. Gene Ontology and KEGG analyses indicated involvement in alcohol metabolism (log₁₀FDR = 3.45), GPCR signaling (log₁₀FDR = 3.36), and hormone regulation (log₁₀FDR = 3.08). Molecular docking showed favorable binding of neoandrographolide to ALDH2 (- 8.7 kcal/mol), with hydrogen bond interactions involving GLU399 and SER246, compared with andrographolide (- 7.9 kcal/mol). Blood-brain barrier assessment indicated andrographin and 14-deoxy-11,12-dehydroandrographolide may access central nervous system targets, while andrographolide aligned with peripheral pathways. In vitro assays showed DPPH radical scavenging activity (90-100% inhibition at 100-300 μg/mL). High-performance thin-layer chromatography confirmed andrographolide integrity (Rf 0.36) in 3D-printed oral film formulations. These findings generate hypotheses regarding andrographolide and its analogs in hangover-associated pathways, with ALDH2 and GABA_A receptors requiring further in vivo and clinical validation.

The online version contains supplementary material available at 10.1007/s40203-026-00625-4.