Emodin derivatives as promising multi-aspect intervention agents for amyloid aggregation: molecular docking/dynamics...

Alzheimer's disease (AD) is a progressive neurodegenerative disease with complex pathogenesis. Despite the pathogenesis is unknown, the misfolding and accumulation of β-amyloid (Aβ) peptide play the important role in the occurrence and development of AD. Hence, multi-aspect intervention of the misfolded Aβ peptides aggregation is a promising therapy for AD. In previous work, we obtained the emodin derivatives (a-d) with multifunctional anti-AD activities, including metal ions chelation, cholinesterase inhibition, and hydroxyl/superoxide anion radical elimination. In this work, we predicted the interaction of emodin derivatives (a-d) with Aβ by combining molecular docking simulation and molecular dynamics simulation, and evaluated the ability to intervene with the self-, Cu²⁺- and AChE-induced Aβ aggregation via in vitro methods. The results indicated that a-d could act as the potent multi-aspect intervention agents for Aβ aggregation. In addition, a-d could effectively eliminate peroxyl radical, had virtually no neurotoxicity, and protect cells from oxidative and Aβ-induced damage. The prediction results of ADMET properties showed that a-d had suitable pharmacokinetic characteristics. It suggested that a-d could act as the promising multi-targeted directed ligands (MTDLs) for AD. These results may provide meaningful information for the development of the potential MTDLs for AD which are modified from natural-origin scaffolds.