Identification of Catechins’ Binding Sites in Monomeric A<i>β</i><sub>42</sub> through Ensemble Docking and MD Simulations
The assembly of the amyloid-<i>β</i> peptide (A<i>β</i>) into toxic oligomers and fibrils is associated with Alzheimer’s disease and dementia. Therefore, disrupting amyloid assembly by direct targeting of the A<i>β</i> monomeric form with small molecules or antibo...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-05-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/9/8161 |
| Summary: | The assembly of the amyloid-<i>β</i> peptide (A<i>β</i>) into toxic oligomers and fibrils is associated with Alzheimer’s disease and dementia. Therefore, disrupting amyloid assembly by direct targeting of the A<i>β</i> monomeric form with small molecules or antibodies is a promising therapeutic strategy. However, given the dynamic nature of A<i>β</i>, 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<i>β</i><sub>42</sub>. It is shown that both hydrophobic aromatic interactions and hydrogen bonding are crucial for the binding of catechins to A<i>β</i><sub>42</sub>. Additionally, it has been found that all the studied ligands, especially <i>EGCG</i>, can act as potent inhibitors against amyloid aggregation by blocking the central hydrophobic region of A<i>β</i>. 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<i>β</i>. |
|---|---|
| ISSN: | 1661-6596 1422-0067 |