Chronotherapeutic Potential of Withania somnifera Phytocompounds for Narcolepsy Management: An Integrated GC-MS and In Silico Study

Objective: To investigate the chronotherapeutic potential of phytochemicals from <i>Withania somnifera</i> (ashwagandha) leaf extract as histamine H3 receptor (H3R) inhibitors for suppressing H3R overexpression to manage excessive daytime sleepiness (EDS) and muscle weakness (cataplexy) in narcolepsy.Methods: Gas chromatography–mass spectrometry (GC-MS) was used to identify 43 phytoconstituents in <i>W. somnifera</i> leaf extract. Molecular docking was performed to evaluate H3R-binding affinity of these compounds. Physicochemical properties, drug-likeness, blood-brain barrier permeability, and the absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis were done to evaluate drug-like characteristics. Molecular dynamics simulations and molecular mechanics/generalized Born surface area (MM/GBSA) calculations were conducted to validate binding stability, and protein-ligand interactions were visualized to identify key binding mechanisms.Results: GC-MS analysis identified major compounds, including 2-methoxy-4-vinylphenol and hexadecanoic acid. Molecular docking revealed methotrexate, 1,2-benzenedicarboxylic acid, octadecenoic acid, adenosine 3',5'-cyclic monophosphate, and 9,12-octadecadienoyl chloride as top H3R-binding candidates with docking scores ranging from -8.8 to -6.2 kcal/mol. Methotrexate and adenosine 3',5'-cyclic monophosphate exhibited favorable stability and safety profiles in ADMET analyses. Molecular dynamics and MM/GBSA confirmed stable binding, with key hydrogen bonds and hydrophobic interactions observed with H3R residues.Conclusion: Phytochemicals from <i>W. somnifera</i>, particularly methotrexate, 1,2-benzenedicarboxylic acid, and adenosine 3',5'-cyclic monophosphate, show promise as novel plant-based H3R inhibitors for managing EDS and cataplexy in narcolepsy. These findings support their potential as safer alternatives to current treatments; nevertheless, further in vivo clinical validation is needed.