A Docking Score Function for Estimating Ligand-Protein Interactions: Application to Acetylcholinesterase Inhibition

Authors

Jianxin Guo
Margaret M. Hurley
Jeffery B. Wright
Gerald H. Lushington

Date of this Version

2004

Comments

Published in J. Med. Chem. 2004, 47, 5492-5500.

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-oneout 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.