Crystal structure of human acetylcholinesterase in complex with tacrine: Implications for drug discovery

Int J Biol Macromol. 2022 Jun 15:210:172-181. doi: 10.1016/j.ijbiomac.2022.05.009. Epub 2022 May 6.


Alzheimer's disease (AD) is one of the most common, progressive neurodegenerative disorders affecting the aged populations. Though various disease pathologies have been suggested for AD, the impairment of the cholinergic system is one of the critical factors for the disease progression. Restoration of the cholinergic transmission through acetylcholinesterase (AChE) inhibitors is a promising disease modifying therapy. Being the first marketed drug for AD, tacrine reversibly inhibits AChE and thereby slows the breakdown of the chemical messenger acetylcholine (ACh) in the brain. However, the atomic level of interactions of tacrine towards human AChE (hAChE) is unknown for years. Hence, in the current study, we report the X-ray structure of hAChE-tacrine complex at 2.85 Å resolution. The conformational heterogeneity of tacrine within the electron density was addressed with the help of molecular mechanics assisted methods and the low-energy ligand configuration is reported, which provides a mechanistic explanation for the high binding affinity of tacrine towards AChE. Additionally, structural comparison of reported hAChE structures sheds light on the conformational selection and induced fit effects of various active site residues upon binding to different ligands and provides insight for future drug design campaigns against AD where AChE is a drug target.

Keywords: Alzheimer's disease; Conformational flexibility; Crystal structure; Human acetylcholinesterase; MM-GBSA; Tacrine.

MeSH terms

  • Acetylcholinesterase / metabolism
  • Aged
  • Alzheimer Disease* / drug therapy
  • Alzheimer Disease* / metabolism
  • Cholinesterase Inhibitors / chemistry
  • Drug Discovery
  • Humans
  • Ligands
  • Molecular Structure
  • Tacrine* / chemistry
  • Tacrine* / pharmacology
  • Tacrine* / therapeutic use


  • Cholinesterase Inhibitors
  • Ligands
  • Tacrine
  • Acetylcholinesterase