Antiemetic Efficacy of Nodakenin Through Muscarinic, Dopaminergic, and Serotonergic Receptor Modulation: Combined Experimental and Computational Approach.

The goal of this study was to assess the antiemetic activity of nodakenin (NOD) in a chick model using CuSO4.5H2O (50 mg/kg; per orally (p.o.)) to induce emesis and to assess the underlying mechanism via in vivo and silico approaches. NOD was administered orally at three doses of 5, 10, and 20 mg/kg body weight. Conversely, hyoscine (HYO-21), ondansetron (OND-5), and domperidone (DOM-6) were supplied orally as positive controls (PCs). Distilled water (DW) containing 0.9% NaCl and 0.5% Tween 80 was utilized as a negative control (NC) group. PCs and NOD-10 were given to the chicks either separately or in combination to determine whether they had antagonistic or synergistic effects. Molecular docking and visualization of ligand-receptor interactions against D2, D3, 5-HT3, and M1-M5 receptors were performed using computational tools, alongside pharmacokinetic (PK) and drug-likeness assessments of the selected ligands. In vivo results displayed that NOD reduced retches (8 ± 2.09 times) and enhanced latency (106.2 ± 4.46 s) in chicks at middle doses, with better antiemetic effects in combination therapy with HYO. In silico results showed that NOD has the strongest binding affinity (BA) against the D2, 5-HT3, and M4 receptors with scores of − 9.6, − 7.8, and − 9.8 kcal/mol through the creation of hydrogen bonds (HBs) and also showed an acceptable PK profile. In conclusion, NOD exhibits potent antiemetic effects through modulation of muscarinic receptors, warranting further investigation.