Chronotherapeutic Potential of Withania somnifera Phytocompounds for Narcolepsy Management: An Integrated GC-MS and In Silico Study
Abstract
Objective: To investigate the chronotherapeutic potential of phytochemicals from Withania somnifera (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 W. somnifera 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…
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