Loading...

Molecular Dynamics Simulation of Aβ42 Neurotoxicity Inhibition in Order to Alzheimer’s Disease Treatment

Khandan, Vahid | 2015

809 Viewed
  1. Type of Document: M.Sc. Thesis
  2. Language: Farsi
  3. Document No: 46821 (08)
  4. University: Sharif University of Technology
  5. Department: Mechanical Engineering
  6. Advisor(s): Firoozabadi, Bahar; Saeedi, Mohammad Saeed
  7. Abstract:
  8. Alzheimer’s disease (AD) is the most common type of dementia in the elderly. The neuropathology and treatment of AD is not precisely determined yet, but according to the pathological studies, AD is associated with presence of toxic soluble oligomers and insoluble senile plaques formed by amyloidosis of Amyloid Beta (Aβ) in neocortical region of brain. An attractive therapeutic approach to treat AD is to identify small ligands that are capable of binding to critical residues in order to inhibit or reverse Aβ amyloidosis process as source of neurotoxicity. In this area, therapeutic efforts designed various organic agents and most of them focused on the N-terminal sequence of Aβ. The aim of present study is to investigate inhibitory effects of a penta-peptide on all the Aβ toxicities from peptide aggregation to membrane insertion. This penta-peptide have the sequence G33LMVG37 from C-terminal of Aβ. Present research identify cryptic and allosteric binding sites of Penta-peptide as a ligand to five specified domains of Aβ (D1AEFRHD7, K16LVFFAE22, V24GSNKGAIIGLMV36, M35VGGVVIV42 and V40IV42) using combined Docking and Molecular dynamics simulation. Binding free energies in practical sites are determined with Alchemical route using FEP and ABF calculations. The simulation identified six stable sites for process of penta peptide binding to Aβ42 as an inhibitor. This result indicate that this penta-peptide is capable to inhibit aggregation process and can be consider as an AD drug for preclinical studies. The impediment of these pathophysiological processes by a small peptide could be helpful in altering the progress of AD and other conformational diseases like cancer, diabetes and extra neurodegeneration disorders
  9. Keywords:
  10. Molecular Dynamic Simulation ; Alzheimer ; Amyloid Inhibitors ; Docking

 Digital Object List

 Bookmark

No TOC