Theses (Master in Healthcare Informatics and Analytics)

Alzheimer’s Disease (AD) is a fatal neurodegenerative disorder marked by cognitive decline. Current treatment offers limited relief but do not later the progression of the disease. This study employs Molecular Dynamics (MD) simulation to investigate drug repurposing for hyperphosphorylated tau (HP Tau) protein, an important factor in AD as it damages neurons, produces tangles, and spreads resulting in cognitive decline. The binding affinities and interactions of another three top ranked repurposed drugs : Deoxycorticosterone Acetate (DOCA), Nitrazepam (NTZ) and Testosterone Cypionate (TPCC) that was selected in previous docking studies among 7 other repurposed drugs were evaluated based on their interactions to the protein HP Tau using MD simulations like thermodynamic properties and structural properties like Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), Radius of Gyration (RoG) and Hydrogen Bond (HB) analysis. The simulations demonstrated sustained drug-protein interactions, suggesting their potential to inhibit HP Tau aggregation. DOCA provided moderate stability with a large number of structural interactions, NTZ has multiple binding sites due to its increased hydrogen bonds, which are consistent with its modulatory effects on cognitive function and the hypothalamic-pituitary-adrenal axis associated with AD. This study emphasises drug repurposing, facilitated by MD simulations, as a cost-effective strategy for identifying new AD treatments. By targeting HP Tau, these drugs offer promising avenues for halting the progression of AD, offering hope in the fight against this incurable disease. Keywords: Alzheimer’s Disease, Ligands, Molecular Docking, Molecular Dynamics Simulation, Drug repurposing, Root Mean Square Deviation, Hydrogen Bonding, Radius of Gyration, Root Mean Square Fluctuation

Alzheimer disease (AD) is a progressive degenerative disorder of the brain resulting in the loss of higher cognitive function and is considered as the most common form of dementia. AD is characterised by a triad of pathological changes in the brain and there have been many proposed approaches and research aimed at treating AD. The two hallmark substrates causing the cognitive decline in AD are the amyloid beta (Aβ) plaques deposition, and the neurofibrillary tangles of hyperphosphorylated (HP) tau. In recent years, the focus on research has been based on the Aβ hypothesis. However, the failed clinical drug trials targeting Aβ suggest that tau related therapies may be a more viable approach to AD treatment. This study aims to analyse the binding affinity of Teniposide and Testosterone Enanthate as potential repurposed drug candidates acting as aggregation inhibitors of HP tau protein to prevent the formation of neurofibrillary tangles (NFT) which might stop the progression of AD. The binding interactions between the two proposed drugs with the HP tau protein was analysed by conducting 20 ns molecular dynamics (MD) simulation. Thermodynamics properties, root mean squared deviation (RMSF), root mean squared fluctuation (RMSF), radius of gyration (RoG) and hydrogen bond (HB) analysis were conducted on the trajectories of the MD simulation. The findings from this study suggested that Teniposide is the better potential compound in inhibiting the aggregation of HP tau protein and should be analysed further with a longer simulation, inclusion of MMGB/PBSA calculation and 2D/3D interaction images to ensure higher reliability.