Identification of Inhibitors for Amyloid-beta in Alzheimer's Disease and Cerebral Amyloid Angiopathy

The neurodegenerative illness Alzheimer's disease causes 70% of cases of dementia, leading to the impairment of behavioral and cognitive functions such as language, attention, memory, judgment, and reasoning. The disease is caused by the buildup of amyloid fibrils in brain neurons. Recently, in 2023, a new type of amyloid fibril extracted from the leptomeninges of Alzheimer’s disease patients has been resolved. This structure has a different shape and size than the earlier 2019 structure. We hypothesize that since the two structures are different, the ligands binding and inhibiting the structure should also be different. Therefore, a rigorous research process was undertaken, including molecular docking simulations to identify inhibitors that can bind at the fibril interface and prevent fibril formation. A total of 8216 ligands were docked on the amyloid protein, and the best five ligands based on the binding interactions were selected for further evaluation. These results were further validated using a machine-learning technique called P2Rank. Finally, molecular docking and molecular dynamics simulations in the protein-fibril complex were performed to understand the interactions between amyloid peptide/fibril and the plasma membrane. The thoroughness of our research process instills confidence in the potential of developing inhibitors that can prevent fibril formation, potentially leading to new treatments for the disease.