Identification of Catechins’ Binding Sites in Monomeric Aβ(42) through Ensemble Docking and MD Simulations

The assembly of the amyloid-β peptide (Aβ) into toxic oligomers and fibrils is associated with Alzheimer’s disease and dementia. Therefore, disrupting amyloid assembly by direct targeting of the Aβ monomeric form with small molecules or antibodies is a promising therapeutic strategy. However, given the dynamic nature of Aβ, 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 Aβ(42). It is shown that both hydrophobic aromatic interactions and hydrogen bonding are crucial for the binding of catechins to Aβ(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 Aβ. 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 Aβ.