Prediction of the binding sites of huperzine A in acetylcholinesterase by docking studies

Yuan-Ping Pang, Alan P. Kozikowski

Research output: Contribution to journalArticle

108 Citations (Scopus)

Abstract

We have performed docking studies with the SYSDOC program on acetylcholinesterase (AChE) to predict the binding sites in AChE of huperzine A (HA), which is a potent and selective, reversible inhibitor of AChE. The unique aspects of our docking studies include the following: (i) Molecular flexibility of the guest and the host is taken into account, which permits both to change their conformations upon binding. (ii) The binding energy is evaluated by a sum of energies of steric, electrostatic and hydrogen bonding interactions. In the energy calculation no grid approximation is used, and all hydrogen atoms of the system are treated explicitly. (iii) The energy of cation-π interactions between the guest and the host, which is important in the binding of AChE, is included in the calculated binding energy. (iv) Docking is performed in all regions of the host's binding cavity. Based on our docking studies and the pharmacological results reported for HA and its analogs, we predict that HA binds to the bottom of the binding cavity of AChE (the gorge) with its ammonium group interacting with Trp84, Phe330, Glu199 and Asp72 (catalytic site). At the the opening of the gorge with its ammonium group partially interacting with Trp279 (peripheral site). At the catalytic site, three partially overlapping subsites of HA were identified which might provide a dynamic view of binding of HA to the catalytic site.

Original languageEnglish (US)
Pages (from-to)669-681
Number of pages13
JournalJournal of Computer-Aided Molecular Design
Volume8
Issue number6
DOIs
StatePublished - Dec 1994

Fingerprint

Binding sites
Acetylcholinesterase
Binding Sites
predictions
Binding energy
Catalytic Domain
canyons
Ammonium Compounds
electrostatic bonding
binding energy
cavities
Cholinesterase Inhibitors
Conformations
Electrostatics
Hydrogen Bonding
Hydrogen bonds
Static Electricity
Positive ions
inhibitors
energy

Keywords

  • Acetylcholinesterase inhibitors
  • Alzheimer's disease
  • Molecular recognition
  • SYSDOC

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

Prediction of the binding sites of huperzine A in acetylcholinesterase by docking studies. / Pang, Yuan-Ping; Kozikowski, Alan P.

In: Journal of Computer-Aided Molecular Design, Vol. 8, No. 6, 12.1994, p. 669-681.

Research output: Contribution to journalArticle

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