Molecular insights into the inhibitory mechanism of bi-functional bis-tryptoline triazole against β-secretase (BACE1) enzyme.

The β-site amyloid precursor protein-cleaving enzyme 1 (β-secretase, BACE1) is involved in the formation of amyloid-β (Aβ) peptide that aggregates into soluble oligomers, amyloid fibrils, and plaques responsible for the neurodegeneration in Alzheimer disease (AD). BACE1 is one of the prime therapeutic targets for the design of inhibitors against AD as BACE1 participate in the rate-limiting step in Aβ production. Jiaranaikulwanitch et al. reported bis-tryptoline triazole (BTT) compound as a potent inhibitor against BACE1, Aβ aggregation as well as possessing metal chelation and antioxidant activity. However, the molecular mechanism of BACE1 inhibition by BTT remains unclear. Thus, molecular docking and molecular dynamics (MD) simulations were performed to elucidate the inhibitory mechanism of BTT against BACE1. MD simulations highlight that BTT interact with catalytic aspartic dyad residues (Asp32 and Asp228) and active pocket residues of BACE1. The hydrogen-bond interactions, hydrophobic contacts, and π-π stacking interactions of BTT with flap residues (Val67-Asp77) of BACE1 confine the movement of the flap and help to achieve closed (non-active) conformation. The PCA analysis highlights lower conformational fluctuations for BACE1-BTT complex, which suggests enhanced conformational stability in comparison to apo-BACE1. The results of the present study provide key insights into the underlying inhibitory mechanism of BTT against BACE1 and will be helpful for the rational design of novel inhibitors with enhanced potency against BACE1.