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.