Identification of Catechins Binding Pockets in Monomeric Aβ₄₂Through Ensemble Docking and MD Simulations

Abstract

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 pockets in monomeric Aβ42. It is shown that both hydrophobic aromatic interactions and hydrogen bonding are crucial for the binding of catechins to Aβ42. 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 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.

Interactions of Curcumin’s Degradation Products with the Aβ42 Dimer: A Computational Study

“…Similarly, vanillin interacts predominantly with residue sequences 9 GY 10 , 19 FF 20 , and 33 GLMVGG 38 (Figure 2b). Both ligands share the interaction hot spots along the sequence of Aβ 42 (regions of 19 FF 20 , 34 LMVGG 38 , and 9 GY 10 ), which indicates the homogeneity of the Aβ 42 dimer molecular recognition sites across the ligands. Importantly, the hot spot regions 19 FF 20 and 34 LMVGG 38 are part of the central hydrophobic cluster (CHC) and the C-terminus hydrophobic region, respectively, which drive Aβ fibrillization.…”

“…Both ligands share the interaction hot spots along the sequence of Aβ 42 (regions of 19 FF 20 , 34 LMVGG 38 , and 9 GY 10 ), which indicates the homogeneity of the Aβ 42 dimer molecular recognition sites across the ligands. Importantly, the hot spot regions 19 FF 20 and 34 LMVGG 38 are part of the central hydrophobic cluster (CHC) and the C-terminus hydrophobic region, respectively, which drive Aβ fibrillization. 87−97 In line with the contact number analysis, the analysis obtained from ensemble docking (Figures S7−S12 in the Supporting Information) indicates that the ligands attach primarily to the CHC region, particularly to its aromatic residues (F19 and F20).…”

“…The other lower-ranked poses were selected since sometimes the pose with the lowest RMSD relative to the experimental pose is not captured by Vina. 19 To select the high-ranked complexes, ΔΔG binding was defined as the difference of binding free energy between the top-ranked pose and the lower-ranked pose (ΔG toppose − ΔG lower-rankedpose ). Different cutoff values of ΔΔG binding (0.1, 0.2, and 0.3 kcal/mol) were used for selecting the generated docking complexes (Table 1).…”

Interactions of curcumin’s degradation products with the Aβ42 dimer: A computational study

“…The top scoring pose for each run is related to the complex with the most favorable binding free energy. The other lower-ranked poses were selected since sometimes the pose with the lowest RMSD relative to the experimental pose is not captured by Vina (14). To select the high- ranked complexes, ΔΔG binding was defined as the difference of binding free energy between top-ranked pose and the lower-ranked pose (ΔG top pose ‒ ΔG lower-ranked pose ).…”

“…Therefore, preventing or reducing the aggregation of the Aβ is an effective therapeutic strategy against AD. In recent years, small molecules have been developed as inhibitors to intervene in the formation of higher order aggregates of Aβ (12)(13)(14)(15)(16)(17)(18).…”