Journal of Computer-Aided Molecular Design

, Volume 33, Issue 5, pp 521–530 | Cite as

Discovery of new multifunctional selective acetylcholinesterase inhibitors: structure-based virtual screening and biological evaluation

  • Cheng-Shi Jiang
  • Yong-Xi Ge
  • Zhi-Qiang Cheng
  • Jia-Li Song
  • Yin-Yin Wang
  • Kongkai ZhuEmail author
  • Hua ZhangEmail author


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.


AChE inhibitor Pharmacophore model Molecular docking Anti-Aβ aggregation Neuroprotective activity 



This research work was financially supported by the National Natural Science Foundation of China [Nos. 21672082, 81803438], Shandong Key Development Project [No. 2016GSF201209], the Young Taishan Scholars Program [No. tsqn20161037], Natural Science Foundation of Shandong Province [Nos. ZR201807060857, ZR2017BH038, JQ201721], and Shandong Talents Team Cultivation Plan of University Preponderant Discipline [No. 10027].

Compliance with ethical standards

Conflicts of interest

The authors have declared no conflict of interest.

Supplementary material

10822_2019_202_MOESM1_ESM.doc (29 mb)
Supplementary material 1 (DOC 29688 kb)


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.School of Biological Science and TechnologyUniversity of JinanJinanPeople’s Republic of China
  2. 2.Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghaiPeople’s Republic of China

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