Experimental and computational investigation of the binding mechanism of thymol with human transferrin: Importance of dietary phytochemicals in Alzheimer's disease therapeutics

Abstract

Transferrin (Tf) regulates free iron in the body, which is critical to shield the body from the detrimental effects of free iron, a potent neurotoxin, in the aerobic surroundings of the blood and body fluids. Maintaining iron homeostasis is essential because any disruption in its homeostasis ultimately results in the generation of iron-triggered oxidative stress that is further implicated in the pathogenesis of numerous diseases, including Alzheimer's disease (AD). In recent times, plant extracts and plant-derived phytochemicals have gained importance in the field of drug design and discovery. The present study aimed to comprehensively explore the interaction of thymol with Tf, owing to the pivotal roles played by Tf and thymol in AD. Initially, the details of the binding of thymol with Tf were assessed employing docking and all-atom molecular dynamics (MD) simulation studies for 300 ns in detail. It was found that thymol binds to Tf with a good affinity, forming close interactions with key residues, specifically within Tf's hydrogen carbonate and iron-binding domain. Moreover, the binding of thymol did not cause any significant structural changes in the Tf conformation, implying the Tf-thymol complex stability. The results of UV visible and fluorescence spectroscopic studies supported strong binding of thymol with Tf, signifying the stability of the Tf-thymol complex. The study provided valuable insights into the binding mechanisms, structural stability, and conformational dynamics of the Tf-thymol complex, providing a platform to use thymol and its derivatives in AD therapeutics.