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bioRxiv · 10.1101/2022.02.09.479729

Identification of Catechins Binding Pockets in Monomeric Aβ42 Through Ensemble Docking and MD Simulations

Chavez Gracia, C.·Firouzi, R.·Sowlati-Hashjin, S.·Ashouri, M.·Karimi-Jafari, M. H.·Karttunen, M.
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Abstract

The assembly of the Amyloid-{beta} peptide (A{beta}) into toxic oligomers and fibrils is associated with Alzheimers disease and dementia. Therefore, disrupting amyloid assembly by direct targeting of the A{beta} monomeric form with small molecules or antibodies is a promising therapeutic strategy. However, given the dynamic nature of A{beta}, 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 pockets 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. Also, it has been found that all the studied ligands, especially the EGCG, can act as potent inhibitors against amyloid aggregation by blocking the central hydrophobic region of the A{beta}. 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}.

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Chavez Gracia, C., Firouzi, R., Sowlati-Hashjin, S., Ashouri, M., Karimi-Jafari, M. H., Karttunen, M.. 2022-02-10. Identification of Catechins Binding Pockets in Monomeric Aβ42 Through Ensemble Docking and MD Simulations. https://doi.org/10.1101/2022.02.09.479729

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