Emodin derivatives as promising multi-aspect intervention agents for amyloid aggregation: molecular docking/dynamics simulation, bioactivities evaluation, and cytoprotection.

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. [ABSTRACT FROM AUTHOR]