Cooperative hydrogen bonds and mobility of the non-aromatic ring as selectivity determinants for human acetylcholinesterase to similar anti-Alzheimer's galantaminics: a computational study

J Biomol Struct Dyn. 2019 Apr;37(7):1843-1856. doi: 10.1080/07391102.2018.1470036. Epub 2018 May 17.


Galantamine (Gnt) is a natural alkaloid inhibitor of acetylcholinesterase and is presently one of the most used drugs in the treatment against Alzheimer's disease during both the initial and intermediate stages. Among several natural Gnt derivatives, sanguinine (Sng) and lycoramine (Lyc) attract attention because of the way their subtle chemical differences from Gnt lead to drastic and opposite distinctions in inhibitory effects. However, to date, there is no solved structure for these natural derivatives. In the present study, we applied computational modeling and free energy calculation methods to better elucidate the molecular basis of the subtle distinctions between these derivatives and Gnt. The results showed that differences in the mobility of the non-aromatic ring carried by the Lyc-like sp2-sp3 modification display drastic conformational, vibrational, and entropic penalties at binding compared to Gnt. Additionally, the establishment of a stronger hydrogen bond network added enthalpic advantages for the linkage of the Sng-like methoxy-hydroxy substituted ligands. These results, which suggest an affinity ranking in agreement with that found in the literature, provided insights that are helpful for future planning and development of new anti-Alzheimer's disease drugs.

Keywords: AD: Alzheimer’s disease; AchE: acetylcholinesterase; Alzheimer disease; Gnt: Galantamine; Hyb: Hybrid compound between Lyc and Sng; Lyc: Lycoramine; MD: Molecular dynamics; MM/GBSA: Molecular mechanics/Generalized Born and surface area continuum solvation; MM/PBSA: Molecular mechanics/Poisson-Boltzmann and surface area continuum solvation; PDB: Protein Data Bank; RMSD: Root mean square deviation; Sng: Sanguinine; acetylcholinesterase; conformational entropy; free energy, MM/PBSA-GB/PBSA; galantamine; hAchE: Human acetylcholinesterase; molecular dynamics simulation; molecular modeling; selectivity; virtual docking.

MeSH terms

  • Acetylcholinesterase / chemistry*
  • Alzheimer Disease / drug therapy
  • Binding Sites
  • Catalytic Domain
  • Cholinesterase Inhibitors / chemistry*
  • Cholinesterase Inhibitors / pharmacology
  • Humans
  • Hydrogen Bonding
  • Ligands
  • Molecular Conformation*
  • Molecular Docking Simulation*
  • Molecular Dynamics Simulation*
  • Molecular Structure
  • Protein Binding


  • Cholinesterase Inhibitors
  • Ligands
  • Acetylcholinesterase