Next Article in Journal
Synthesis, Characterization, and Bacterial Fouling-Resistance Properties of Polyethylene Glycol-Grafted Polyurethane Elastomers
Previous Article in Journal
The Contribution of the Immune System in Bone Metastasis Pathogenesis
Article

Discovery of Novel Acetylcholinesterase Inhibitors as Potential Candidates for the Treatment of Alzheimer’s Disease

Division of Life Science, Division of Applied Life Science (BK21 Plus), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Jinju 52828, Korea
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(4), 1000; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20041000
Received: 14 January 2019 / Revised: 12 February 2019 / Accepted: 21 February 2019 / Published: 25 February 2019
(This article belongs to the Section Molecular Pharmacology)
Acetylcholinesterase (AChE) catalyzes the hydrolysis of neurotransmitter acetylcholine to acetate and choline in a synaptic cleft. Deficits in cholinergic neurotransmitters are linked closely with the progression of Alzheimer’s disease (AD), which is a neurodegenerative disorder characterized by memory impairment, and a disordered cognitive function. Since the previously approved AChE inhibitors, donepezil (Aricept), galantamine (Reminyl), and rivastigmine (Exelon), have side effects and several studies are being carried out out to develop novel AD drugs, we have applied a three-dimensional quantitative structure−activity relationship (3D QSAR) and structure-based pharmacophore modeling methodologies to identify potential candidate inhibitors against AChE. Herein, 3D QSAR and structure-based pharmacophore models were built from known inhibitors and crystal structures of human AChE in complex with donepezil, galantamine, huperzine A, and huprine W, respectively. The generated models were used as 3D queries to screen new scaffolds from various chemical databases. The hit compounds obtained from the virtual screening were subjected to an assessment of drug-like properties, followed by molecular docking. The final hit compounds were selected based on binding modes and molecular interactions in the active site of the enzyme. Furthermore, molecular dynamics simulations for AChE in complex with the final hits were performed to evaluate that they maintained stable interactions with the active site residues. The binding free energies of the final hits were also calculated using molecular mechanics/Poisson-Boltzmann surface area method. Taken together, we proposed that these hits can be promising candidates for anti-AD drugs. View Full-Text
Keywords: acetylcholinesterase; Alzheimer’s disease; molecular docking; molecular dynamics simulation; pharmacophore modeling acetylcholinesterase; Alzheimer’s disease; molecular docking; molecular dynamics simulation; pharmacophore modeling
Show Figures

Graphical abstract

MDPI and ACS Style

Son, M.; Park, C.; Rampogu, S.; Zeb, A.; Lee, K.W. Discovery of Novel Acetylcholinesterase Inhibitors as Potential Candidates for the Treatment of Alzheimer’s Disease. Int. J. Mol. Sci. 2019, 20, 1000. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20041000

AMA Style

Son M, Park C, Rampogu S, Zeb A, Lee KW. Discovery of Novel Acetylcholinesterase Inhibitors as Potential Candidates for the Treatment of Alzheimer’s Disease. International Journal of Molecular Sciences. 2019; 20(4):1000. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20041000

Chicago/Turabian Style

Son, Minky, Chanin Park, Shailima Rampogu, Amir Zeb, and Keun W. Lee 2019. "Discovery of Novel Acetylcholinesterase Inhibitors as Potential Candidates for the Treatment of Alzheimer’s Disease" International Journal of Molecular Sciences 20, no. 4: 1000. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20041000

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop