Coumarin Prevents the Oligomerization and Aggregation of Amylid β: Deciphering the Mode of Action using Molecular Simulations

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Neurological disorders (NDs) affect 15% of the human population globally, causing cognitive and physical disabilities. There is an increase in cases of NDs with the aging populations that challenges accessible healthcare. NDs, like Parkinson’s, and Alzheimer’s, cause neuronal loss and impairments. Misfolded protein accumulation characterizes disorders like Alzheimer’s and Parkinson’s. Amyloid beta (A[Formula: see text] has two main variants, A[Formula: see text] and A[Formula: see text]. A[Formula: see text] accumulation triggers microglia activation, and synaptic loss in Alzheimer’s disease (AD). A[Formula: see text] induces neuronal damage, forming amyloid plaques. Soluble A[Formula: see text] oligomers are neurotoxic, disrupting neuronal functions. Therefore, A[Formula: see text] aggregation inhibition is a potential therapeutic strategy for AD. Molecular dynamics (MD) simulations offer unique insights, especially for investigating structural changes in peptides like A[Formula: see text] interacting with inhibitors. Computational methods provide insights into the driving forces behind the aggregation of monomeric proteins at early stages. Using computational methods, this study explores how coumarin inhibits A[Formula: see text] oligomerization and aggregation, revealing reduced [Formula: see text]-sheet formation and potential drug development insights. Coumarin interacted at the high aggregation propensity and hydrophobic region of A[Formula: see text] and stabilized it. When 10 molecules A[Formula: see text] were simulated, [Formula: see text]-sheet content stood at 2.27% within the initial 5 ns, progressively reaching 11.35% until 50 ns. This upward trend continued, reaching an average [Formula: see text]-sheet content as 22.83% for entire simulation. However, the introduction of 250 mM coumarin during the simulation diminished the formation of [Formula: see text]-sheets to 10.59%. Overall, our studies suggest that coumarin could serve as a potential preventive and therapeutic agent for inhibiting A[Formula: see text] oligomerization and aggregation.