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- Title
Effects Of Donepezil On The Structure Of Amyloid β-Peptide: A Molecular Dynamics Simulation Study.
- Authors
Zakaria, Norzalina; Mohammad Latif, Muhammad Alif; Azaman, Siti Norani; Mat Azmi, Intan Diana; Hassan, Nadiatul Hafiza; Abdul Rahman, Mohd Basyaruddin; Faujan, Nur Hana
- Abstract
Introduction: The accumulation of amyloid beta (Aβ) plays a crucial role in the onset and progression of Alzheimer’s disease (AD), a chronic neurodegenerative disorder. In AD patients, abnormal interactions and misfolded Aβ42 are being extensively explored as important pathogenic events. Donepezil, an acetylcholinesterase (AChE) inhibitor is FDA-approved drug for AD treatment. However, the binding mechanisms of donepezil with Aβ42 monomer have not yet been clearly identified at the atomic level. We investigated the conformational dynamics and the binding interaction between donepezil with Aβ42 by molecular dynamics (MD) simulation. This study provides significant insights in understanding detailed Aβ42 peptide structural changes in the presence of the donepezil and their binding mechanisms. Methods: MD simulations for Aβ42-APO (control) and Aβ42-DPZ systems were performed using the GROMACS 5.1.4 package with the GROMOS96 54A7 force field for 100 ns. Both systems were solvated with a simple point charge (SPC) water model. The resulting trajectories were analyzed using the inbuilt GROMACS tools along with the visual molecular dynamics (VMD) and the dictionary of secondary structure of proteins (DSSP) program. Results: The Aβ42-DPZ forms a stable complex with RMSD <2.0 Å and showed less compact structure compared to Aβ42-APO due to less folded shape. From DSSP analysis, donepezil significantly increased α-helix content while reduced the β-content and turn, suggesting that donepezil was successfully inhibiting the formation of β-sheet-rich structures and prevent the formation amyloid fibrils. Conclusion: This study showed that the donepezil binds to Aβ42 monomer efficiently and forms a stable complex. Detailed Aβ structural changes upon loss of β-content in the presence of the donepezil are also revealed, which gives further insight at the atomistic level to understand the inhibitory functions of donepezil molecules used in AD treatment. These finding provide key insights into the inhibitory mechanism of donepezil against Aβ42 aggregation in AD.
- Subjects
UNITED States. Food &; Drug Administration; MOLECULAR dynamics; AMYLOID; DONEPEZIL; ACETYLCHOLINESTERASE; PEPTIDES; PROTEIN structure; ALZHEIMER'S disease
- Publication
Malaysian Journal of Medicine & Health Sciences, 2022, Vol 18, p60
- ISSN
1675-8544
- Publication type
Abstract