Mechanistic Insight into the Binding of Huperzine a with Human Transferrin: Computational, Spectroscopic and Calorimetric Approaches

Abstract

Huperzine A (HupA), an alkaloid found in the club moss Huperzia Serrata, has been in use for centuries in Chinese traditional medicine to treat dementia owing to its ability to inhibit the cholinergic enzyme acetylcholinesterase (AChE), thus acting as an acetylcholinesterase inhibitor (AChEI). An imbalance of metal ions in the brain is linked to Alzheimer’s disease (AD) pathology. Transferrin (Tf) is a crucial player in iron homeostasis, thus highlighting its significance in AD. This study explores the plausible binding of HupA with Tf using molecular docking, molecular dynamics (MD) simulation, and free energy landscape (FEL) analyses. The docking results show that HupA binds to the functionally active region of Tf by forming three hydrogen bonds with Thr392, Glu394, and Ser688 and several hydrophobic interactions. The MD simulation analyses show that HupA binding is stable with Tf, causing minimal changes to the protein conformation. Moreover, principal component analysis (PCA) and FEL also depict the stable binding of HupA with Tf without any significant fluctuations. Further, fluorescence-based binding suggested excellent binding affinity of HupA with Tf affirming in silico observations. Isothermal titration calorimetry (ITC) advocated the spontaneous binding of HupA with Tf. This study provides an insight into the binding mechanism of HupA with Tf, and overall, the results show that HupA, after required experimentations, can be a better therapeutic agent for treating AD while targeting Tf.

Huperzine A-Liposomes Efficiently Improve Neural Injury in the Hippocampus of Mice with Chronic Intermittent Hypoxia

“…Molecular docking molecular dynamics simulation demonstrated HuA could bind with the functionally active region of Tf, providing a direct reason for reducing TBI-depended iron uptake in CNS diseases. 56 In this study, we found that HuA-LIP decreased ferric content and the total iron content, which was superior to solely HuA administration. However, HuA cannot chemically react directly with ferrous and ferric iron ( Figure 7 ).…”

Computational and spectroscopic insight into the binding of citral with human transferrin: Targeting neurodegenerative diseases

“…To assess the binding strength between citral and htf, we conducted a fluorescence-based quenching experiment at different temperatures using a Jasco spectrofluorometer (FP-6200). Our analysis followed established protocols from previous studies [ 21 , 42 , 43 ]. In a bid to ensure accuracy, we corrected “inner filter effect”.…”