Molecular docking and molecular dynamics simulations of compounds targeting GABAA receptor with potential relevance to anesthesia.

The gamma-aminobutyric acid type A (GABAA) receptor is the primary mediator of inhibitory neurotransmission in the central nervous system and represents an important pharmacological target for sedative and anesthetic agents. However, many conventional anesthetics are associated with adverse effects and pharmacokinetic limitations, highlighting the need for safer compounds with improved delivery to the central nervous system and better therapeutic profiles. In this study, natural compounds were evaluated as potential modulators of the GABAA receptor using an integrated computational approach. Molecular docking was performed using AutoDock Vina, followed by pharmacokinetic and drug-likeness evaluation using SwissADME and molecular dynamics simulations to examine binding stability. Several phytochemicals exhibited docking scores comparable to the sedative drug zolpidem (-7.1 to -7.6 kcal/mol). However, pharmacokinetic predictions indicated that most natural compounds had limited ability to cross the blood-brain barrier despite favorable gastrointestinal absorption. Zolpidem was therefore used as a reference compound capable of penetrating the central nervous system to evaluate the pharmacokinetic requirements necessary for effective receptor targeting. Molecular dynamics simulations demonstrated stable receptor-ligand interactions and structural stability of the complex throughout the trajectory. These findings highlight the importance of integrating binding affinity with pharmacokinetic feasibility when prioritizing candidate modulators of the GABAA receptor. Although several natural compounds showed promising interaction profiles, further structural optimization and experimental validation are required.