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<p>Anxiety is one of the most common mental health disorders today, often leading to panic, restlessness, and tension. Conventional treatments can cause adverse effects, prompting interest in plant-based alternatives. Glycowithanolides from <i>Withania somnifera</i> (WSGs) have demonstrated neuroprotective effects, but their role in anxiety management remains underexplored. This study evaluates the anxiolytic potential of WSGs using an integrated computational approach combining pharmacokinetic profiling, network pharmacology, molecular docking, and molecular dynamics (MD) simulations. Eleven WSGs exhibited favorable blood–brain barrier permeability and drug-likeness, complying with Lipinski’s Rule of Five. Network pharmacology revealed key interactions between WSGs and anxiolytic pathways such as cAMP, Ras, and calcium signaling, as well as addiction-related pathways. Genes like GRIN1, CHRM1, NFKB1, and HDAC2 emerged as potential targets, with GRIN1 identified as the central hub. Molecular docking of the WSGs with GRIN1 (PDB ID: 5EWM) indicated strong binding affinities, and the best-scoring ligand–receptor complex was further evaluated through MD simulations to assess stability and interactions. Results suggest strong binding of WSGs to GRIN1 and indicate a potential modulatory role; however, the proposed mechanism remains hypothesis-generating and requires experimental validation. Overall, this study highlights the therapeutic promise of glycowithanolides in managing anxiety disorders and offers a mechanistic basis for future experimental validation.</p><p></p>

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Deciphering the anxiolytic mechanism of glycowithenolides from Withania somnifera: insights from network pharmacology, molecular docking, and simulation studies

  • 期刊论文

  • 发表日期：

    2026年5月11日

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  • Monosiz Rahaman,
  • Sourav Ghosh

摘要

Anxiety is one of the most common mental health disorders today, often leading to panic, restlessness, and tension. Conventional treatments can cause adverse effects, prompting interest in plant-based alternatives. Glycowithanolides from Withania somnifera (WSGs) have demonstrated neuroprotective effects, but their role in anxiety management remains underexplored. This study evaluates the anxiolytic potential of WSGs using an integrated computational approach combining pharmacokinetic profiling, network pharmacology, molecular docking, and molecular dynamics (MD) simulations. Eleven WSGs exhibited favorable blood–brain barrier permeability and drug-likeness, complying with Lipinski’s Rule of Five. Network pharmacology revealed key interactions between WSGs and anxiolytic pathways such as cAMP, Ras, and calcium signaling, as well as addiction-related pathways. Genes like GRIN1, CHRM1, NFKB1, and HDAC2 emerged as potential targets, with GRIN1 identified as the central hub. Molecular docking of the WSGs with GRIN1 (PDB ID: 5EWM) indicated strong binding affinities, and the best-scoring ligand–receptor complex was further evaluated through MD simulations to assess stability and interactions. Results suggest strong binding of WSGs to GRIN1 and indicate a potential modulatory role; however, the proposed mechanism remains hypothesis-generating and requires experimental validation. Overall, this study highlights the therapeutic promise of glycowithanolides in managing anxiety disorders and offers a mechanistic basis for future experimental validation.