Exploring the Role of EGCG as Aβ-42 Inhibitor: An In Silico Study on hIAPP Octamer Destabilization

Abstract

Amyloid beta is an abnormally folded protein that aggregates in the lipid bilayers of brain cells. This causes structural disruption in the brain, contributing to Alzheimer’s disease. It exists in various forms, starting as monomers, oligomers (including dimers, trimers, tetramers, and more). It then aggregates into protofibrils and, finally, fibrils. Of these, Aβ-42 is more toxic than Aβ-40, making it a significant target for Alzheimer’s research. Strategies that disrupt Aβ-42 may provide potential treatments for AD. At present, natural compounds are emerging as a focus in combating toxic compounds involved in neurodegenerative disease. The presence of diverse functional groups and distinct molecular structures contributes to therapeutic potential. Among the catechins present in green tea extracts, epigallocatechin-3-gallate (EGCG) exhibits the strongest antioxidant property. This highlights its potential in neuroprotective drug discovery. In this work, we performed the molecular dynamics simulations to investigate the molecular interactions between EGCG and the target hIAPP. In the first part, we did a comparative analysis of widely used force fields. It was found that the CHARMM-27 force field is most reliable for maintaining the beta-sheet organization. In the second part of the study, a 200 ns simulation revealed that EGCG forms various strong binding interactions with the hIAPP, resulting in disruption of its beta-sheet structure. The hydroxyl groups and aromatic rings of EGCG interact with the hIAPP more firmly. It disrupts the intra-peptide bonds of protein structure. The structural features and biochemical activity of EGCG make it a promising lead compound. It can be used to create novel, potent, and effective analogues to treat Alzheimer's disease.