- Title
- Inhibitor search and variant analysis of Acetylcholinesterase
- Creator
- Ras, Harnaud
- Subject
- Acetylcholinesterase
- Subject
- Alzheimer's disease
- Subject
- Acetylcholinesterase -- Inhibitors
- Subject
- Alzheimer's disease -- Chemotherapy
- Subject
- Cerebrovascular disease -- Treatment
- Subject
- Molecular mechanics Poisson–Boltzmann surface area (MM-PBSA)
- Date Issued
- 2021-04
- Date
- 2021-04
- Type
- thesis
- Type
- text
- Type
- Masters
- Type
- MSc
- Identifier
- http://hdl.handle.net/10962/178191
- Identifier
- vital:42919
- Description
- Acetylcholinesterase (AChE) inhibition is used to treat Alzheimer's disease by increasing the availability of acetylcholine to carry nerve signals in the brain. The response to this treatment varies widely, which may be due to altered affnity to the current drugs caused by genetic variation. Various negative side-effects limit their use. As this is one of the only available therapeutic drug targets to treat Alzheimer's disease, decreasing the negative effects is of great importance. AChE is involved in biological processes that occur after acute ischemic stroke. Stroke is the third leading cause of death worldwide, and 87% of all stroke cases belong to ischemic stroke. AchEI (cholinesterase inhibitors) have been suggested to have properties that lower the risk of stroke. AChE is one of 15 verified drug targets under study for treatment of stroke. In addition to Alzheimer's disease and stroke, Lewy body disease (LBD) may be treated using cholinesterase inhibitors. The goals of this study are to find inhibitors that can potentially be used to treat Alzheimer's disease and/or stroke and to investigate variants which may affect protein dynamics and function. Two variants were analyzed, P247L and T229S. Molecular simulation of the P247L variant resulted in a disruption in protein dynamics in comparison to the wildtype. A total of 5728 molecules were screened and 10 nanosecond simulations were used to narrow down the set of compounds. The four best performing molecules were simulated for 10 nanoseconds. MM-PBSA was performed to identify molecules with high binding free energies.
- Description
- Thesis (MSc) -- Faculty of Science, Biochemistry and Microbiology, 2021
- Format
- computer
- Format
- online resource
- Format
- application/pdf
- Format
- 1 online resource (96 pages)
- Format
- Publisher
- Rhodes University
- Publisher
- Faculty of Science, Biochemistry and Microbiology
- Language
- English
- Rights
- Ras, Harnaud
- Rights
- All Rights Reserved
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RU Department of Biochemistry and Microbiology (2015-)
| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | SOURCE1 | RAS-MSC-TR21-121.pdf | 3 MB | Adobe Acrobat PDF | View Details Download |