Theoretical studies of Alzheimer's disease drug candidate 3-[(2,4-dimethoxy)benzylidene]-anabaseine (GTS-21) and its derivatives

Biochem Biophys Res Commun. 2005 Dec 16;338(2):1059-64. doi: 10.1016/j.bbrc.2005.10.047. Epub 2005 Oct 21.

Abstract

Theoretical and molecular modeling studies have been conducted for understanding the details of how 3-[(2,4-dimethoxy)benzylidene]-anabaseine dihydrochloride (GTS-21) and its metabolism derivatives bind with the receptor of alpha7 nicotinic acetylcholine dimer. Good accordance with experimental results has been achieved. It was found that the van der Waals repulsion makes the dominant contribution to the binding energy. GTS-21 and its metabolites are apparently too large for the binding sites of the alpha7 dimer. To improve the effectiveness of the drug, a possible approach is to reduce its volume while maintaining the presence of the active groups. Our studies, in combination with experimental studies, will lead to a promising basis for practical drug design against Alzheimer's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Benzylidene Compounds / analysis
  • Benzylidene Compounds / chemistry*
  • Binding Sites
  • Brain Chemistry
  • Computer Simulation
  • Dimerization
  • Drug Delivery Systems / methods*
  • Drug Design*
  • Humans
  • Models, Chemical*
  • Models, Molecular*
  • Molecular Conformation
  • Protein Binding
  • Pyridines / analysis
  • Pyridines / chemistry*
  • Receptors, Nicotinic / analysis
  • Receptors, Nicotinic / chemistry*
  • Sequence Analysis, Protein
  • alpha7 Nicotinic Acetylcholine Receptor

Substances

  • Benzylidene Compounds
  • Chrna7 protein, human
  • Pyridines
  • Receptors, Nicotinic
  • alpha7 Nicotinic Acetylcholine Receptor
  • 3-(2,4-dimethoxybenzylidene)anabaseine