Background: β-site amyloid precursor protein cleaving enzyme (BACE 1) is the ratelimiting
enzyme in the formation of neurotoxic β-amyloid (Aβ) residues (Aβ1-40 or Aβ1-42)
considered as key players in the onset of Alzheimer’s Disease (AD). Consequently, BACE 1 is one
of the principal targets of anti-AD therapy with many small molecule BACE 1 inhibitors (BACE
1Is) in clinical trials. AZD3293 (Lanabecestat) is a BACE 1I that concluded in phase 2/3 clinical
trials. Due to the limited knowledge about the interaction of this drug with the BACE 1 enzyme, in
the present study, we performed comprehensive Molecular Dynamics (MD) analysis to understand
the binding mechanism of AZD3293 to BACE 1.
Methods: A production run of 120 ns is carried out and results are analysed using Root Mean
Square Deviation (RMSD), root mean square fluctuation (RMSF), and radius of gyration (Rg) to
explain the stability of enzyme ligand complex. Further, the distance (d1) between the flap tip
(Thr72) and the hinge residue of the flexible loop (Thr328), in relation to θ1 (Thr72–Asp228-
Thr328), and to the dihedral angle δ (Thr72-Asp35-Asp228-Thr328) were measured.
Results: The presence of the ligand within the active site restricted conformational changes as
shown by decreased values of RMSF and average RMSD of atomic positions when compared to the
values of the apoenzyme. Further analysis via the flap dynamics approach revealed that the
AZD3293 decreases the flexibility of binding residues and made them rigid by altering the
Conclusion: The prospective binding modes of AZD3293 from this study may extend the
knowledge of the BACE 1-drug interaction and pave the way to design analogues with similar
inhibitory properties needed to slow the progression of Alzheimer’s disease.