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

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

Author information

1
Molecular Graphics and Modeling Lab, University of Kansas, Lawrence, Kansas 66045, USA.

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.

PMID:
15481986
DOI:
10.1021/jm049695v
[Indexed for MEDLINE]

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