Repurposing drugs for inhibition of hyperphosphorylated tau protein in alzheimer’s disease: Molecular modelling studies

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. It 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. The purpose of this study aims to discover hyperphosphorylated tau protein inhibitor by repurposing the available drugs on the market and subsequently, study its potentials using various molecular modelling methods. The work started with homology modelling on its conserved region, followed by virtual screening of repurposed drugs that could pass through the blood brain barrier. Subsequently, molecular docking was performed on the hyperphosphorylated tau model, and the potential inhibitors identified from the virtual screening. Molecular dynamics simulation was performed to further optimise hyperphosphorylated tau model and top 2 ranked compounds from docking studies. The findings from this study suggested that a potential repurposed drug list that could be potential compounds in inhibiting the aggregation of HP tau protein and can be further explored being a potential treatment for AD.