Characterization of a Ligand−Receptor Binding Event Using Receptor-Dependent Four-Dimensional Quantitative Structure−Activity Relationship Analysis

Receptor-dependent four-dimensional quantitative structure−activity relationship (RD-4D-QSAR) analysis is used to map the ligand−receptor binding event characteristic of a set of 47 glucose analogue inhibitors of glycogen phosphorylase (GPb). Specifically, the geometric and energetic binding profiles are constructed, conformational changes are determined, and conformational couplings among structural units are identified for the composite set of ligand−receptor complexes. A pruned ligand−receptor model is used to estimate ligand−receptor thermodynamics. Rather than explicitly handling the large amount of structural data generated from each of the pruned ligand−receptor models, these complexes were divided into three subregions. The subregions consist of a “functional” region, the smallest region providing definitive information about inhibitor binding, and two “allosteric” regions that surround the “functional” region and are based on distances from the center of the catalytic site. Maximum information on...