In Vivo and In Silico Evaluation of the Sedative Effect of Trilobatin via the GABAergic Pathway Using the Thiopental Sodium‐Induced Sleep Model in Mice

Insomnia is a prevalent neuropsychiatric disorder characterized by difficulty in initiating and maintaining sleep. Trilobatin (TLB), a naturally occurring flavonoid, possesses diverse pharmacological properties, including antioxidant, anti‐inflammatory, neuroprotective, and antidepressant activities. This study investigates the sedative potential of TLB, a natural dihydrochalcone glycoside, via the GABAergic pathway using both in vivo and in silico approaches. Swiss albino mice were subjected to behavioral tests (open field, hole cross) and a thiopental sodium (TPS)‐induced sleep model following TLB administration at doses of 5, 10, and 20 mg/kg, alone and in combination with diazepam (DZP). TLB significantly reduced sleep latency (8.52 ± 0.52 min at 20 mg/kg vs. 56.4 ± 18.01 min in control) and increased sleep duration (167.6 ± 6.94 min vs. 11 ± 6.34 min), in a dose‐dependent manner. The combination of TLB (10 mg/kg) with DZP (2 mg/kg) produced the most pronounced effect, with the shortest latency (1.66 ± 0.21 min) and longest sleep duration (204.8 ± 15.73 min). Molecular docking revealed strong binding affinity of TLB to the GABA A receptor (−6.6 kcal/mol), comparable to DZP (−7.0 kcal/mol). In silico ADMET profiling indicated favorable drug‐likeness and low toxicity for TLB. These results demonstrate that TLB exerts significant sedative effects, potentially through GABA A receptor modulation, supporting its potential as a natural sedative agent with a promising safety profile.