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.