Structural and molecular insights into tacrine-benzofuran hybrid induced inhibition of amyloid-β peptide aggregation and BACE1 activity

Amyloid-β (Aβ) aggregation and β-amyloid precursor protein cleaving enzyme 1 (BACE1) are the potential therapeutic drug targets for Alzheimer's disease (AD). A recent study highlighted that tacrine-benzofuran hybrid C1 displayed anti-aggregation activity against Aβ₄₂ peptide and inhibit BACE1 activity. However, the inhibition mechanism of C1 against Aβ₄₂ aggregation and BACE1 activity remains unclear. Thus, molecular dynamics (MD) simulations of Aβ₄₂ monomer and BACE1 with and without C1 were performed to inspect the inhibitory mechanism of C1 against Aβ₄₂ aggregation and BACE1 activity. In addition, a ligand-based virtual screening followed by MD simulations was employed to explore potent new small-molecule dual inhibitors of Aβ₄₂ aggregation and BACE1 activity. MD simulations highlighted that C1 promotes the non aggregating helical conformation in Aβ₄₂ and destabilizes D23-K28 salt bridge that plays a vital role in the self-aggregation of Aβ₄₂. C1 displays a favourable binding free energy (-50.7 ± 7.3 kcal/mol) with Aβ₄₂ monomer and preferentially binds to the central hydrophobic core (CHC) residues. MD simulations highlighted that C1 strongly interacted with the BACE1 active site (Asp32 and Asp228) and active pockets. The scrutiny of interatomic distances among key residues of BACE1 highlighted the close flap (non-active) position in BACE1 on the incorporation of C1. The MD simulations explain the observed high inhibitory activity of C1 against Aβ aggregation and BACE1 in the in vitro studies. The ligand-based virtual screening followed by MD simulations identified CHEMBL2019027 (C2) as a promising dual inhibitor of Aβ₄₂ aggregation and BACE1 activity.Communicated by Ramaswamy H. Sarma.