Exploring the Molecular Interactions of Galantamine with Human Transferrin: In-silico and In vitro Insight

Abstract The iron transporter protein, Transferrin (Tf), is a glycoprotein that binds and mediates the Iron (Fe) transport through blood plasma. It has a significant role in transporting Fe in the endosomal compartment of the cells by forming complexes of Fe-Tf-TfR (Transferrin receptor). The role of Tf in AD pathogenesis is not so clear and needs to be explored, but it has been linked to the activity of COX-2 in rats with diabetic neuropathy. Galantamine is a moderate inhibitor of Acetylcholinesterase (AChE) isolated from Galanthus woronowii. Here we have explored the possible interactions of Tf and Galantamine using computational as well as experimental approaches. First, we have performed molecular docking of Galantamine with Tf to predict their binding affinity and possible interactions. The molecular docking study was further escorted by all-atom molecular dynamics (MD) simulations for 100ns followed by principal component analysis. MD studies suggested that the Tf-Galantamine docked complex is stable throughout the simulation trajectory. The computational results were further entrenched by a fluorescence-based binding study that suggested moderate binding of Galantamine with Tf with a binding constant of 104 M-1. Isothermal titration calorimetry (ITC) further validated the spontaneous binding of Galantamine to Tf. This study provides a platform and can be implicated in Alzheimer’s disease (AD) therapy.