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PubMed · 15481986

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

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

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AcetylcholinesteraseBinding SitesCholinesterase InhibitorsCrystallography, X-RayDonepezilHumansIndansLigandsModels, MolecularMolecular StructureMutagenesis, Site-DirectedPiperidinesProtein BindingQuantitative Structure-Activity RelationshipJournal ArticleResearch Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, Non-P.H.S.Research Support, U.S. Gov't, P.H.S.

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Jianxin Guo, Margaret M Hurley, Jeffery B Wright, Gerald H Lushington. 2004-10-21. A docking score function for estimating ligand-protein interactions: application to acetylcholinesterase inhibition.. https://doi.org/10.1021/jm049695v

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