Elucidating the Interaction of Human Ferritin with Quercetin and Naringenin: Implication of Natural Products in Neurodegenerative Diseases: Molecular Docking and Dynamics Simulation Insight

[Image: see text] Recent research has advocated the significant contribution of metal dyshomeostasis in developing and progressing Alzheimer’s disease (AD). Disruption of homeostasis creates an imbalance of the metal ions that causes neuronal dysfunction and death. Flavonoids such as quercetin and naringenin play an essential role in iron homeostasis and are widely explored in treating various complex diseases. Iron is a critical player in many physiological activities, and hence, its homeostasis is essential for the normal functioning of the brain. Iron deficiency and iron overload contribute to AD development, highlighting the importance of maintaining iron homeostasis. Ferritin is an iron protein associated with the storage and sequestration of excess ferrous iron, playing a pivotal role in maintaining iron levels. Flavonoids are the most common polyphenolic compounds present in the human diet and are known to exert multiple neuroprotective actions. Naringenin and quercetin are extensively explored polyphenols having a broad range of therapeutic potential ranging from cancers to neurodegenerative disorders. This study aims to investigate their binding, employing molecular docking and molecular dynamics (MD) simulation in light of these polyphenols’ and ferritin’s therapeutic importance in AD. In this study, we performed structure-based docking of quercetin and naringenin with human ferritin. First, the binding affinity of quercetin and naringenin toward ferritin was estimated, and then their close interactions were explored to find the stable poses. All-atom 100 ns MD simulations further escorted the docking study, followed by principal component and free energy landscape analyses. The dynamic studies helped investigate the conformational dynamic, structural stability, and interaction mechanism of ferritin with quercetin and naringenin. The MD analysis suggested that the binding of quercetin and naringenin with ferritin stabilizes throughout the simulation period and leads to fewer conformational deviations. This study gives an insight at the atomistic level into the interaction between quercetin and naringenin with ferritin, thereby aiding in understanding the activity and mechanism of protein and drug binding. The study is clinically significant as iron participates in the occurrence of AD.