- Title
- Structure and interaction studies of beta-amyloid in the search for new lead compounds for the treatment of Alzheimer’s disease
- Creator
- Mtini, Onke
- ThesisAdvisor
- Lobb, Kevin A
- Subject
- Alzheimer's disease -- Chemotherapy
- Subject
- Alzheimer's disease -- Treatment
- Subject
- Amyloid beta-protein
- Subject
- Oxidative stress
- Subject
- Protein binding
- Subject
- South African Natural Compounds Database
- Date
- 2020
- Type
- Thesis
- Type
- Masters
- Type
- MSc
- Identifier
- http://hdl.handle.net/10962/167574
- Identifier
- vital:41493
- Description
- Alzheimer’s disease (AD) is the most devastating neurodegenerative disorder that effects the aging population worldwide. In this study three hypotheses of AD are explored, the β-amyloid cascade hypothesis, the β-amyloid metal binding hypothesis and the oxidative stress hypothesis are explored. In the first case compounds from the South African Natural Compounds Database (SANCDB) are docked to models of β-amyloid fibrils and the properties of these fibrils under pulling simulations are compared to a known small molecule disruptor of β-amyloid, wgx-50. In these simulations SANCDB compounds are identified that disrupt β-amyloid in a similar manner to wgx-50. In these simulations the disruption to the free energy of binding of chains to the fibrils is quantified. For metal binding and oxidative stress hypotheses, problems in simulation arise due to only fragments of β-amyloid being present in the Research Collaboratory for Structural Bioinformatics protein data bank (RCSB PDB), as determined from NMR experiments. In this work, β-amyloid is set up under periodic boundary conditions to simulate a fibril under reasonable computational time. Within these periodic boundary conditions, β-amyloid has been solvated in copper and zinc rich environments and diffusion of these metals around the fibrils has been explored. The localization of these metals (in simulation only using van der Waal’s and electrostatic terms) around the fibril has led us to explore other possible metal binding sites. Metal bound to the infinite fibril has been optimized at the QM/MM level and some of the reactive oxygen species in the presence of the fibril are quantified.
- Format
- 137 pages, pdf
- Publisher
- Rhodes University, Faculty of Science, Biochemistry and Microbiology
- Language
- English
- Rights
- Mtini, Onke
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RU Department of Biochemistry and Microbiology (2015-)
| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details | SOURCE1 | MTINI-MSC-TR20-393.pdf | 2 MB | Adobe Acrobat PDF | View Details |