A docking score function for estimating ligand-protein interactions: application to acetylcholinesterase inhibition.
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.
Molecular Graphics and Modeling Lab, University of Kansas, Lawrence, Kansas 66045, USA.
Jianxin
J
Guo
Margaret M
MM
Hurley
Jeffery B
JB
Wright
Gerald H
GH
Lushington
D000110:Acetylcholinesterase / Q000737:chemistry* / Q000235:genetics; D001665:Binding Sites; D002800:Cholinesterase Inhibitors / Q000737:chemistry*; D018360:Crystallography, X-Ray; D000077265:Donepezil; D006801:Humans; D007189:Indans / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D016297:Mutagenesis, Site-Directed; D010880:Piperidines / Q000737:chemistry; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship
D002800:Cholinesterase Inhibitors; D007189:Indans; D008024:Ligands; D010880:Piperidines; D000077265:Donepezil; D000110:Acetylcholinesterase