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Investigation of Amyloid-Beta Inhibition using Multifunctional Peptide Drugs Associated with Metal Ions

Asadbegi, Mohsen | 2020

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  1. Type of Document: Ph.D. Dissertation
  2. Language: Farsi
  3. Document No: 53483 (08)
  4. University: Sharif University of Technology
  5. Department: Mechanical Engineering
  6. Advisor(s): Shamloo, Amir
  7. Abstract:
  8. Many experimental and theoretical studies have suggested that zinc binding to Aβ could promote amyloid-β aggregation and reactive oxygen species (ROS) production induced by AD disease. Therefore, the introduction of multifunctional drugs capable of chelating zinc metal ion and inhibiting Aβ aggregation is a promising strategy in the development of AD treatment. In present study molecular docking and molecular dynamics (MD) simulations were used to evaluate the efficacy of two new bifunctional peptide drug, composed of two different domains: C-terminal hydrophobic region of Aβ and Zn2+ chelator region. To evaluate the multifunctionality of the ligands, a comprehensive set of MD simulations up to 8 μs were carried out including Aβ relaxations, ligand-Zn2+ dual interactions and of the most important, ligand-Zn2+-Aβ42 triple interactions. Analysis of the results strongly indicated that the binfunctional ligands can chelate zinc metal ion, avoid Aβ aggregation and dissagregate Aβ oligomers simultaneously. We found that the proposed ligand has considerable hydrophobic and H-bond interactions with monomeric and oligomeric Aβ in the presence of zinc metal ion. Therefore, in addition to prevention of β-sheet formation and protection of α-helix native structure, the α-helical structure of Aβ has increased in the simulations. Furthermore, analysis of the interactions between Ligand-zinc complex and Aβ reveals that the zinc metal ion is coordinated with the chelator region of the ligands and only one residue of Aβ. The results substantiate previous experimental and theoretical findings in the literature about Aβ interactions with zinc metal ion and also Aβ interactions with the first domain of the proposed ligand. Moreover, our novel approach to evaluate the chelation and to calculate the binding free energies was verified with previous experimental and DFT studies
  9. Keywords:
  10. Molecular Dynamic Simulation ; Amyloid Inhibitors ; Drug Design ; Zinc Metal Ion ; Free Energy Calculation ; Multifunctional Peptide ; Alzheimer ; Chelation Therapy

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