Synergistic Antiemetic Effects of Nerolidol on Domperidone, Hyoscine, and Ondansetron: <i>In Vivo</i> and <i>in Silico</i> Investigations on Receptor Binding Affinity

The present study was designed to measure the potential antiemetic properties of nerolidol (NDL) via in vivo and in silico studies. To induce emesis copper sulfate pentahydrate (CuSO₄.5H₂O) was administered at a dose of 50 mg/kg (orally) to 2-day-old chicks. The test sample (NDL) was given at two doses of 50 and 100 mg/kg. b.w. orally. Additionally, aprepitant (16 mg/kg), domperidone (6 mg/kg), hyoscine (21 mg/kg), ondansetron (5 mg/kg), and diphenhydramine (10 mg/kg) were given also orally as positive controls. To observe the modulatory effects of the test sample, combination therapies with reference drugs were also administered to three different groups of animals. Molecular docking and visualization of ligand-receptor interaction were performed against several emesis-inducing receptors (5HT₃, D₂, D₃, H₁, and M₁-M₅) using diverse computational tools. Pharmacokinetics and drug-likeness of the selected ligands were also calculated. Findings demonstrated that NDL significantly (p <0.05) dose-dependently lessens the mean number of retches and delays the emetic onset in the chicks. The combined drug therapy with ondansetron exposed better antiemetic activity. In addition, in silico analysis, NDL has greater binding affinity (-7.3 kcal/mol) against M₂ and M₃ receptors. In conclusion, NDL exerted mild antiemetic activity with synergistic properties through muscarinic receptors.