Identification of Catechins' Binding Sites in Monomeric Aβ42 through Ensemble Docking and MD Simulations

The assembly of the amyloid-beta peptide (A beta) into toxic oligomers and fibrils is associated with Alzheimer's disease and dementia. Therefore, disrupting amyloid assembly by direct targeting of the Ab monomeric form with small molecules or antibodies is a promising therapeutic strategy. However, given the dynamic nature of Ab, standard computational tools cannot be easily applied for high-throughput structure-based virtual screening in drug discovery projects. In the current study, we propose a computational pipeline-in the framework of the ensemble docking strategy-to identify catechins' binding sites in monomeric A beta(42). It is shown that both hydrophobic aromatic interactions and hydrogen bonding are crucial for the binding of catechins to A beta(42). Additionally, it has been found that all the studied ligands, especially EGCG, can act as potent inhibitors against amyloid aggregation by blocking the central hydrophobic region of Ab. Our findings are evaluated and confirmed with multi-microsecond MD simulations. Finally, it is suggested that our proposed pipeline, with low computational cost in comparison with MD simulations, is a suitable approach for the virtual screening of ligand libraries against A beta.Y

Automated summary

The assembly of amyloid-beta peptide (Aβ) into toxic oligomers and fibrils is associated with Alzheimer's disease and dementia. Targeting the monomeric form of Aβ with small molecules or antibodies to disrupt amyloid assembly is a promising therapeutic strategy. This study proposes a computational pipeline, using ensemble docking strategy, to identify catechins' binding sites in monomeric Aβ(42) and explores the crucial interactions for binding. The results suggest that catechins, especially EGCG, can act as potent inhibitors against amyloid aggregation.