Discovery of new acetylcholinesterase inhibitors for Alzheimer's disease: virtual screening and in vitro characterisation

J Enzyme Inhib Med Chem. 2021 Dec;36(1):491-496. doi: 10.1080/14756366.2021.1876685.


For more than two decades, the development of potent acetylcholinesterase (AChE) inhibitors has been an ongoing task to treat dementia associated with Alzheimer's disease and improve the pharmacokinetic properties of existing drugs. In the present study, we used three docking-based virtual screening approaches to screen both ZINC15 and MolPort databases for synthetic analogs of physostigmine and donepezil, two highly potent AChE inhibitors. We characterised the in vitro inhibitory concentration of 11 compounds, ranging from 14 to 985 μM. The most potent of these compounds, S-I 26, showed a fivefold improved inhibitory concentration in comparison to rivastigmine. Moderate inhibitors carrying novel scaffolds were identified and could be improved for the development of new classes of AChE inhibitors.

Keywords: Acetylcholinesterase; Alzheimer disease; inhibition; virtual screening.

MeSH terms

  • Acetylcholinesterase / metabolism*
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Animals
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Donepezil / chemistry
  • Donepezil / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Drug Evaluation, Preclinical
  • Electrophorus
  • Molecular Docking Simulation
  • Molecular Structure
  • Physostigmine / chemistry
  • Physostigmine / pharmacology*
  • Structure-Activity Relationship


  • Cholinesterase Inhibitors
  • Donepezil
  • Physostigmine
  • Acetylcholinesterase

Grants and funding

This work was funded by the state of North-Rhine Westphalia (NRW) and the European Regional Development Fund (EFRE), Project CLIB-Kompetenzzentrum Biotechnologie (CKB) under grant numbers [34-EFRE-0300096] and [34-EFRE-0300097].