Molecular Docking and Dynamics Studies of Withania somnifera Derived Compounds as GABA-A Receptor Modulators for Insomnia

Abstract

Objective: This study aimed to identify potential phytochemicals from <i>Withania somnifera</i> (ashwagandha) that can act as gamma-aminobutyric acid A (GABA-A) receptor agonists or stimulant, and evaluate their suitability as potential insomnia treatments. Methods: Various computational approaches were employed, including virtual screening, biological activity prediction, physicochemical and drug-likeness analysis, absorption, distribution, metabolism, excretion, and toxicity (ADME/T) analysis, and molecular dynamics simulations. The Diseases Plants Eliminate (DISPEL) server was used to identify suitable plant species in context to insomnia, and the Indian Medicinal Plants, Phytochemistry And Therapeutics 2.0 (IMPPAT 2.0) database was utilized to assess the phytochemicals from <i>W. somnifera</i>. Virtual screening was performed using AutoDock Vina, and biological activity prediction was carried out using the Prediction of Activity Spectra for Substances (PASS) web server. The SwissADME webserver was used for physicochemical and drug-likeness analysis, while the ADME/T analysis was conducted using the ADMETlab 2.0 and ProTox 3.0 servers. Molecular dynamics simulations were performed using the WEBGRO Macromolecular Simulations server. Results: The findings revealed that hygrine, tropine, and withasomnine exhibited promising GABA-A receptor agonist activity, favorable drug-likeness properties, low toxicity, and stable receptor-ligand interactions. These phytochemicals demonstrated desirable physiochemical properties, adhering to Lipinski’s rule of five, and exhibited favorable ADME profiles. Molecular dynamics simulations showed stable interactions between the compounds and the GABA-A receptor, with minimal conformational changes and high compactness observed for hygrine and tropine. Conclusion: The phytochemicals hygrine, tropine, and withasomnine from <i>W. somnifera</i> emerged as potential lead compounds for the development of novel insomnia treatments targeting the GABA-A receptor. These findings warrant further investigation through experimental validation and optimization to advance their development as potential therapeutic agents for insomnia.