Identification of Catechins' Binding Sites in Monomeric A β 42 through Ensemble Docking and MD Simulations.

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