Microsecond molecular dynamics simulation of Aß42 and identification of a novel dual inhibitor of Aß42 aggregation and BACE1 activity.

AIM: To study the conformational changes of Aß42 and discover novel inhibitors of both Aß42 aggregation and ß-secretase (BACE1). METHODS: A molecular dynamics (MD) simulation at a microsecond level was performed to explore stable conformations of Aß42 monomer in aqueous solution. Subsequently, structure-based virtual screening was used to search for inhibitors of both Aß42 aggregation and BACE1. Protein purification and in vitro activity assays were performed to validate the inhibition of the compounds identified via virtual screening. RESULTS: The initial α-helical conformation of Aß42, which was unstable in aqueous solution, turned into a ß-sheet mixed with a coil structure through a transient and fully random coil. The conformation of Aß42 mainly comprising ß-sheets and coils structure was used for further virtual screening. Five compounds were identified as inhibitors for Aß42 aggregation, and one of them, AE-848, was discovered to be a dual inhibitor of both Aß42 aggregation and BACE1, with IC50 values of 36.95 µmol/L and 22.70 µmol/L, respectively. CONCLUSION: A helical to ß-sheet conformational change in Aß42 occurred in a 1.8 microsecond MD simulation. The resulting ß-sheet structure of the peptide is an appropriate conformation for the virtual screening of inhibitors against Aß42 aggregation. Five compounds were identified as inhibitors of Aß42 aggregation by in vitro activity assays. It was particularly interesting to discover a dual inhibitor that targets both Aß42 aggregation and BACE1, the two crucial players in the pathogenesis of Alzheimer's disease.