Epigallocatechin Gallate as a State-Dependent Modulator of Amyloid-β: Molecular Simulation-Guided Mechanistic Synthesis for Structure-Based Inhibitor Design

Amyloid-β (Aβ) aggregation is a central mechanistic feature of Alzheimer’s disease, involving heterogeneous conformational ensembles that evolve through monomeric, oligomeric, and fibrillar states. Understanding how small molecules modulate these state-dependent processes remains a major challenge in medicinal chemistry. This review examines the molecular mechanisms by which (-)-epigallocatechin-3-gallate (EGCG) perturbs Aβ aggregation, with a focus on insights derived from molecular dynamics (MD) simulations integrated with experimental data. MD studies employing structural, dynamical, and interaction-based descriptors (e.g., β-sheet content, contact maps, and salt bridge persistence) reveal that EGCG acts as a state-dependent modulator: it redistributes monomeric ensembles by masking aggregation-prone regions, induces topology switching in oligomers that suppresses seeding competence, and destabilizes protofibrillar β-sheet networks through interfacial and node-targeting interactions. Methodological analysis highlights the importance of force field selection, sampling depth, and aggregate model dependence, leading to a hierarchy of mechanistic confidence that distinguishes well-supported trends from model-specific observations. From a medicinal chemistry perspective, EGCG is best interpreted as a mechanistic probe rather than as a lead compound, informing the design of biostable modulators through principles such as bioisosteric replacement, topology control, and interfacial targeting. Collectively, this work provides a framework for translating the state-dependent aggregation mechanisms into rational therapeutic strategies.