Computational Discovery and In Vivo Validation of Fenchone as a Neuroprotective Agent Targeting the D ₂ Dopamine Receptor in Parkinson's Disease

In the present study, we assessed the neuroprotective efficacy of the bicyclic monoterpene fenchone in a rotenone-induced rat model of Parkinson’s disease through integrated in silico and in vivo investigations. Molecular modeling indicated that fenchone is very lipophilic (LogP = 2.40) and contains a mostly hydrophobic pharmacophore. It showed good binding affinity with the dopamine D 2 receptor (-5.84 kcal/mol) and similar results to those obtained from levodopa (-5.7 kcal/mol). The results of density functional theory revealed that fenchone has high chemical hardness (3.175 eV) and a large HOMO-LUMO energy gap (6.35 eV), indicating molecular stability. The stability of the fenchone-dopamine D 2 receptor complex in molecular dynamics for 100 ns was confirmed by stable root mean square deviation values and radius of gyration. In vivo, fenchone (200 mg/kg) treatment significantly improved motor performance by decreasing pole test latency and restoring stair test, wood walk test, wire hang and rotarod performance. Biochemical analyses demonstrated that fenchone normalized dopamine levels; increased the activities of antioxidant markers such as catalase and superoxide dismutase; and reduced glutathione levels while decreasing malondialdehyde levels. Histopathologically, nigral neurons were preserved in the presence of levodopa. Taken together, our results suggest that fenchone has the potential to be a novel multimodal disease-modifying agent for PD by acting on the dopamine D2 receptor and exerting antioxidant and neuroprotective effects.