Understanding the binding mechanism of antagonist (AZD3293) against BACE-1: Molecular insights into alzheimer’s drug discovery

Sphelele Sosibo, Daniel Gyamfi Amoako, Anou Moise Somboro, Darren Delai Sun, Jane Catherine Ngila, Hezekiel Kumalo

Research output: Contribution to journalArticlepeer-review


Background: β-site amyloid precursor protein cleaving enzyme (BACE 1) is the rate limiting 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 ϕ (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 conformational changes. 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.

Original languageEnglish
Pages (from-to)850-857
Number of pages8
JournalLetters in Drug Design and Discovery
Issue number7
Publication statusPublished - 2020


  • AZD3293
  • Alzheimer's disease
  • Antagonist
  • BACE-1
  • Binding mechanism
  • Molecular dynamics

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery


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