An Integrated Approach on the Neuroprotective Effects of Ghrelin by Dietary Restriction: From AlphaFold Prediction, Molecular Simulation, to 6-OHDA Induced semi-Parkinson's Disease Model

Abstract Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by the degeneration of dopaminergic neurons, leading to motor dysfunction. This study explores the therapeutic potential of ghrelin in a 6-OHDA rat model of PD, investigating its neuroprotective effects through in vivo experiments, molecular docking, and AlphaFold predictions. We conducted fasting experiments that demonstrated dietary restriction significantly elevated plasma ghrelin levels, which correlated with reduced motor deficits in PD rats. Network pharmacology identified 21 potential targets of ghrelin, revealing mechanisms such as anti-inflammation and neuroprotection. Molecular docking analysis indicated that ghrelin could bind to key proteins, including caspase-3 and IL-6, at their active sites, facilitating further exploration of its interactions through molecular dynamics simulations. These simulations confirmed the stability of ghrelin-target complexes over 100 ns, suggesting that ghrelin influences the activity of important molecular targets related to PD. The predictive analysis using AlphaFold supported the formation of critical chemical interactions between ghrelin and targets involved in neuroprotection. Our findings suggest that ghrelin not only holds promise as a therapeutic agent in PD but also enhances understanding of its underlying molecular mechanisms.