Destabilization of Alzheimer’s Aβ42 protofibrils with acyclovir, carmustine, curcumin, and tetracycline: Insights from molecular dynamics simulations
One of the most common dementia among neurodegenerative diseases is Alzheimer’s disease (AD). The characteristic symptom of AD is the deposition and aggregation of amyloid-β-peptide in the neural tissue. A number of drug molecules have been suggested for dissolving and destabilizing the amyloid-β (Aβ-fibril. Antiviral drug acyclovir, antineoplastic drug carmustine, antibacterial drug curcumin, and antibiotic tetracycline are supposed to be potential drug molecules for treating AD. Many experimental studies suggest that these drugs can effectively be used as an aggregation inhibitor but the underlying mechanism of inhibition of aggregates is currently unknown. In this study, a series of molecular dynamics simulations have been carried out in order to explain the underlying molecular mechanism of the destabilization of Aβ-protofibrils by acyclovir, carmustine, curcumin, and tetracycline. It is found from our results that all these drugs bind to the interior of the hydrophobic grooves of Aβ-protofibrils and caused destabilization of β-strand of Aβ-protofibrils. All these four drugs bind to the hydrophobic residues of Aβ-protofibrils which leads to the destruction of salt bridges between D23-K28 and causes the opening of two β-strands. These drugs are found to be effective in diminishing Aβ-aggregations and among these four drugs, tetracycline is found to be more effective in diminishing Aβ aggregations. The underlying molecular interactions of these drugs to inhibit Aβ aggregations may give some vision towards the approach of designing the structure-based drugs for AD.