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Published on: June 30, 2023
Discovery of new multifunctional selective acetylcholinesterase inhibitors: structure-based virtual screening and
Cheng-Shi Jiang1, Yong-Xi Ge1, Zhi-Qiang Cheng1
1School of Biological Science and Technology, University of Jinan, Jinan, 250022, People's Republic of China.
Abstract:
Although the mechanism of Alzheimer's disease (AD) is still not fully understood, the development of multifunctional AChE inhibitors remains a research focus for AD treatment. In this study, 48 AChE candidate inhibitors were picked out from SPECS database through a pharmacophore- and molecular docking-based virtual screening. The biological evaluation results indicated that four compounds 7, 29, 41 and 48 with different scaffolds exhibited potent and selective AChE inhibitory activity, with the best IC50 value of 1.62 ± 0.11 μM obtained for 48. Then their mechanism of action, the inhibition on Aβ aggregation, neurotoxicity, and neuroprotective activity against Aβ-induced nerve cell injury were well studied. The binding mode of 48 with AChE was also proposed. The present bioassay results indicated that these multifunctional AChE inhibitors were worth for further structural derivatization to make them the anti-AD lead compounds.
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