A docking score function for estimating ligand-protein interactions: application to acetylcholinesterase inhibition

J Med Chem. 2004 Oct 21;47(22):5492-500. doi: 10.1021/jm049695v.

Abstract

Acetylcholinesterase (AChE) inhibition is an important research topic because of its wide range of associated health implications. A receptor-specific scoring function was developed herein for predicting binding affinities for human AChE (huAChE) inhibitors. This method entails a statistically trained weighted sum of electrostatic and van der Waals (VDW) interactions between ligands and the receptor residues. Within the 53 ligand training set, a strong correlation was found (R2 = 0.89) between computed and experimental inhibition constants. Leave-one-out cross-validation indicated high predictive power (Q2 = 0.72), and analysis of a separate 16-compound test set also produced very good correlation with experiment (R2 = 0.69). Scoring function analysis has permitted identification and characterization of important ligand-receptor interactions, producing a list of those residues making the most important electrostatic and VDW contributions within the main active site, gorge area, acyl binding pocket, and periferal site. These analyses are consistent with X-ray crystallographic and site-directed mutagenesis studies.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetylcholinesterase / chemistry*
  • Acetylcholinesterase / genetics
  • Binding Sites
  • Cholinesterase Inhibitors / chemistry*
  • Crystallography, X-Ray
  • Donepezil
  • Humans
  • Indans / chemistry
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Mutagenesis, Site-Directed
  • Piperidines / chemistry
  • Protein Binding
  • Quantitative Structure-Activity Relationship*

Substances

  • Cholinesterase Inhibitors
  • Indans
  • Ligands
  • Piperidines
  • Donepezil
  • Acetylcholinesterase