Journal of Molecular Modeling

, Volume 17, Issue 6, pp 1401–1412 | Cite as

Docking of the alkaloid geissospermine into acetylcholinesterase: a natural scaffold targeting the treatment of Alzheimer’s disease

  • Jocley Queiroz Araújo
  • Josélia Alencar Lima
  • Angelo da Cunha Pinto
  • Ricardo Bicca de Alencastro
  • Magaly Girão Albuquerque
Original Paper


Pharmacological studies from our group [Lima et al. Pharmacol Biochem Behav 92:508, (2009)] revealed that geissospermine (GSP), the major alkaloid of the bark extract of Brazilian Geissospermum vellosii, inhibits acetylcholinesterases (AChEs) in the brains of rats and electric eels (Electrophorus electricus). However, the binding mode (i.e., conformation and orientation) of this indole-indoline alkaloid into the AChE active site is unknown. Therefore, in order to propose a plausible binding mode between GSP and AChE, which might explain the observed experimental inhibitory activity, we performed comparative automatic molecular docking simulations using the AutoDock and Molegro Virtual Docker (MVD) programs. A sample of ten crystal structures of the Pacific electric ray (Torpedo californica) TcAChE, in complex with ten diverse active site ligands, was selected as a robust re-docking validation test, and also for GSP docking. The MVD results indicate a preferential binding mode between GSP and AChE, in which GSP functional groups may perform specific interactions with residues in the enzyme active site, according to the ligand–protein contacts detected by the LPC/CSU server. Four hydrogen bonds were detected between GSP and Tyr121, Ser122, Ser200, and His440, in which the last two residues belong to the catalytic triad (Ser200···His440···Glu327). Hydrophobic and π–π stacking interactions were also detected between GSP and Phe330 and Trp84, respectively; these are involved in substrate stabilization at the active site. This study provides the basis to propose structural changes to the GSP structure, such as molecular simplification and isosteric replacement, in order to aid the design of new potential AChE inhibitors that are relevant to the treatment of Alzheimer’s disease.


GSP/1DX6 (Molegro Virtual Docker)


Acetylcholinesterase Alzheimer disease Geissospermine Indole-indoline alkaloid Molecular docking Molecular modeling 



We gratefully acknowledge the financial support provided by Brazilian governmental agencies: CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico), CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior), and FAPERJ (Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro).

Supplementary material

894_2010_841_MOESM1_ESM.doc (73 kb)
Figure S1 Chemical 2D structures of the ten ligands (ligand name, ligand PDB ID) complexed with the ten Torpedo californica AChEs listed by the AChE PDB IDs (DOC 73 kb)
894_2010_841_MOESM2_ESM.doc (37 kb)
Table S1 Best docking poses (sorted by total energy) of the GSP into the Torpedo californica AChE obtained using the AutoDock program (DOC 37 kb)
894_2010_841_MOESM3_ESM.doc (36 kb)
Table S2 Best docking poses (sorted by total and Re-Rank energy values) of the GSP into the Torpedo californica AChE obtained using the Molegro Virtual Docker program (DOC 36 kb)


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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Jocley Queiroz Araújo
    • 1
  • Josélia Alencar Lima
    • 2
  • Angelo da Cunha Pinto
    • 2
  • Ricardo Bicca de Alencastro
    • 1
  • Magaly Girão Albuquerque
    • 1
  1. 1.Instituto de Química (IQ), Programa de Pós-Graduação em Química (PPGQu), Laboratório de Modelagem Molecular (LabMMol)Universidade Federal do Rio de Janeiro (UFRJ)Rio de JaneiroBrazil
  2. 2.Instituto de Química (IQ), Programa de Pós-Graduação em Química (PPGQu), Laboratório de Produtos Naturais (Pilab)Universidade Federal do Rio de Janeiro (UFRJ)Rio de JaneiroBrazil

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