Insights into the Interaction Mechanism of Ligands with Aβ42 Based on Molecular Dynamics Simulations and Mechanics: Implications of Role of Common Binding Site in Drug Design for Alzheimer's Disease

Aggregation of β‐amyloid (Aβ) into oligomers and further into fibrils is hypothesized to be a key factor in pathology of Alzheimer's disease (AD). In this study, mapping and docking were used to study the binding of ligands to protofibrils. It was followed by molecular simulations to understand...

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Published in:	Chemical biology & drug design Vol. 86; no. 4; pp. 805 - 812
Main Authors:	Kundaikar, Harish S., Degani, Mariam S.
Format:	Journal Article
Language:	English
Published:	England Blackwell Publishing Ltd 01-10-2015
Subjects:	Alzheimer Disease - drug therapy Alzheimer Disease - metabolism Alzheimer's disease Amyloid - antagonists & inhibitors Amyloid beta-Peptides - chemistry Amyloid beta-Peptides - metabolism Aβ42 Binding Sites curcumin docking Drug Design florbetapir Humans Ligands Molecular Dynamics Simulation molecular mechanics molecular simulation Peptide Fragments - chemistry Peptide Fragments - metabolism thioflavin T docking Aβ42 molecular mechanics drug design molecular simulation florbetapir thioflavin T Alzheimer's disease curcumin
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Summary:	Aggregation of β‐amyloid (Aβ) into oligomers and further into fibrils is hypothesized to be a key factor in pathology of Alzheimer's disease (AD). In this study, mapping and docking were used to study the binding of ligands to protofibrils. It was followed by molecular simulations to understand the differences in interactions of known therapeutic agents such as curcumin, fluorescence‐based amyloid staining agents such as thioflavin T, and diagnostic agents such as florbetapir (AV45), with Aβ protofibrils. We show that therapeutic agents bind to and distort the protofibrils, thus causing destabilization or prevention of oligomerization, in contrast to diagnostic agents which bind to but do not distort such structures. This has implications in the rational design of ligands, both for diagnostics and therapeutics of AD. Our study reveals a single preferential binding site (shown in grey) for all the currently known ligands on the NMR solution structure of Aβ protofibrils, which can be used in rationalizing structure based drug design of diagnostics or therapeutics for Alzheimer's disease. Differences in the interactions of known ligands was observed, correlating to their distinct modes of activity as therapeutics or diagnostics.
Bibliography:	Figure S1. Ligands known to bind to Aβ peptides used in the study. Figure S2. SiteMap images of representative ligand in the statistically significant ligand binding Site 2. Figure S3. Validation of docking using literature-based inhibition constants (Ki). Figure S4. Comparative binding modes for ThT (A), curcumin (B), and florbetapir (C) to 2BEG from docking studies at Site2. Table S5. Molecular mechanics energy calculations table. Figure S6. Hydrophobic surface map of 2BEG protofibril showing curcumin binding to the grooves on chainE. Figure S7. Aggregation prone surface near chain E i.e. lower view shown in red. Figure S8. RMSD backbone fluctuation analysis of Curcumin (red), AV45 (blue) and ThT (green) during the 151.2 ns molecular dynamics production run. Table S9. Calculated average backbone RMSD values after each of the MD simulations (Plot shown as Fig 4). Figure S10. Backbone RMSF plots and ligand contact analysis for the last stage of 151.2 ns run for (10A) Curcumin, (10B) AV45, and (10C) ThT. Figure S11. Protein ligand interaction analysis of curcumin. Figure S12. Protein ligand contact analysis of curcumin. Figure S13. Protein ligand interaction analysis of AV45. Figure S14. Protein ligand contact analysis of AV45. Figure S15. Protein ligand interaction analysis of ThT. Figure S16. Protein ligand contact analysis of ThT. Figure S17. Intra-strand Asp23-Lys28 Cα-Cα distance analysis (A-E) for chainA to chainE respectively. Figure S18. Inter strand Asp23-Asp23 Cα-Cα distance analysis. Figure S19. Backbone RMSD differences between the full length Aβ1-42 and Aβ17-42 protofibril fragment for Curcumin. Figure S20. Backbone RMSF for full length Aβ1-42 on curcumin binding. Figure S21. Backbone RMSD differences between the full length Aβ1-42 and Aβ17-42 protofibril fragment for florbetapir. Figure S22. Backbone RMSF for full length Aβ1-42 on florbetapir binding. Figure S23. Backbone RMSD differences between the full length Aβ1-42 and Aβ17-42 protofibril fragment for ThT. Figure S24. Backbone RMSF for full length Aβ1-42 on ThT binding. ark:/67375/WNG-G0VPWK1V-N istex:1CF3ECE220A1ED2DF6EFFB680E8ECC6BCF506D65 ArticleID:CBDD12555 TEQIP UGC CAS ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1747-0277 1747-0285
DOI:	10.1111/cbdd.12555