Experimental and Computational Insights into the Molecular Interactions between Human Transferrin and Apigenin: Implications of Natural Compounds in Targeting Neuroinflammation

Neuroinflammation plays a vital role in Alzheimer’s disease (AD) pathogenesis and other neurodegenerative disorders (NDs). Presently, only symptomatic treatments are available and no disease-modifying drugs are available for AD and other NDs. Thus, targeting AD-associated neuroinflammation with anti-inflammatory compounds and antioxidants has recently been given much focus. Now, flavonoids are being increasingly investigated as therapeutic agents to treat inflammation; apigenin has a neuroprotective effect. Iron dyshomeostasis plays a key role in sustaining the neuroinflammatory phenotype, highlighting the importance of maintaining iron balance, in which human transferrin (HTF) plays a vital role in this aspect. Herein, we explored the binding and dynamics of the HTF–apigenin complex using multifaceted computational and experimental approaches. Molecular docking revealed that apigenin occupies the iron-binding pocket of HTF, forming hydrogen bonds with critical residues Arg475 and Thr686. Molecular dynamics simulations deciphered a dynamic view of the HTF–apigenin complex’s behavior (300 ns) and suggested that the complex maintained a relatively stable conformation. The results of spectroscopic observations delineated significant binding of apigenin with HTF and stable HTF–apigenin complex formation. The observed binding mechanism and conformational stability could pave the way for developing novel therapeutic strategies to target neuroinflammation by apigenin in the context of iron homeostasis.