Molecular simulations of potential agents and targets of Alzheimer’s disease
- Authors: Carlisle, Tanya
- Date: 2020
- Subjects: Alzheimer's disease -- Treatment , Alzheimer's disease -- Molecular aspects , Amyloid beta-protein precurs , Amyloid beta-protein
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/140025 , vital:37825
- Description: The World Alzheimer Report statedin 2016 that approximately 46.8 million people were living with dementia and this figure is expected to triple by 2050. Alzheimer’s Disease was discovered to be a precursor to dementia in 1976 and since then efforts to understand Alzheimer’s have been prioritized. To date, there are very few effective forms of treatment for Alzheimer’s, many are known to offer only mild calming of the symptoms and have side effects such as diarrhea, nausea, loss of appetite and sleep disturbances. This has been due to lack of understanding on how Alzheimer’s is caused. With the two main hallmarks of the disease now being more understood it has opened the doorway into the discovery of new treatments for this disease. This study focuses on the hallmark involving the aggregation of the β-amyloid protein to form plaques surrounding the neurons of the brain. Copper, Zinc and Iron have also been found in high concentrations in and surrounding these plaques. This study focused on the screening of the South African Natural Compound database (SANCDB) to discover hits that have potential destabilizing action against the Beta-amyloid aggregate. If one of these compounds could prove to have destabilizing action on the aggregate it could open the doorway to new potential forms of treatment. Over 700 SANCDB compounds were docked, and the top hits were taken to molecular dynamics to further study the interactions of the compounds and the aggregate. However, the hits identified had strong binding to the aggregate causing it to become stable instead of the desired effect of destabilizing the structure. This information, however, does not rule out the possibility of these compounds preventing the formation of the aggregates. Further, interactions of copper with β-amyloid and copper were determined by solubilizing the aggregate and introducing copper ions in a dynamics simulation. Possible interactions between copper and the methionine residues were visualised.
- Full Text:
- Authors: Carlisle, Tanya
- Date: 2020
- Subjects: Alzheimer's disease -- Treatment , Alzheimer's disease -- Molecular aspects , Amyloid beta-protein precurs , Amyloid beta-protein
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/140025 , vital:37825
- Description: The World Alzheimer Report statedin 2016 that approximately 46.8 million people were living with dementia and this figure is expected to triple by 2050. Alzheimer’s Disease was discovered to be a precursor to dementia in 1976 and since then efforts to understand Alzheimer’s have been prioritized. To date, there are very few effective forms of treatment for Alzheimer’s, many are known to offer only mild calming of the symptoms and have side effects such as diarrhea, nausea, loss of appetite and sleep disturbances. This has been due to lack of understanding on how Alzheimer’s is caused. With the two main hallmarks of the disease now being more understood it has opened the doorway into the discovery of new treatments for this disease. This study focuses on the hallmark involving the aggregation of the β-amyloid protein to form plaques surrounding the neurons of the brain. Copper, Zinc and Iron have also been found in high concentrations in and surrounding these plaques. This study focused on the screening of the South African Natural Compound database (SANCDB) to discover hits that have potential destabilizing action against the Beta-amyloid aggregate. If one of these compounds could prove to have destabilizing action on the aggregate it could open the doorway to new potential forms of treatment. Over 700 SANCDB compounds were docked, and the top hits were taken to molecular dynamics to further study the interactions of the compounds and the aggregate. However, the hits identified had strong binding to the aggregate causing it to become stable instead of the desired effect of destabilizing the structure. This information, however, does not rule out the possibility of these compounds preventing the formation of the aggregates. Further, interactions of copper with β-amyloid and copper were determined by solubilizing the aggregate and introducing copper ions in a dynamics simulation. Possible interactions between copper and the methionine residues were visualised.
- Full Text:
Structure and interaction studies of beta-amyloid in the search for new lead compounds for the treatment of Alzheimer’s disease
- Authors: Mtini, Onke
- Date: 2020
- Subjects: Alzheimer's disease -- Chemotherapy , Alzheimer's disease -- Treatment , Amyloid beta-protein , Oxidative stress , Protein binding , South African Natural Compounds Database
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/167574 , 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.
- Full Text:
- Authors: Mtini, Onke
- Date: 2020
- Subjects: Alzheimer's disease -- Chemotherapy , Alzheimer's disease -- Treatment , Amyloid beta-protein , Oxidative stress , Protein binding , South African Natural Compounds Database
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/167574 , 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.
- Full Text:
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