Prediction of Ligand−Receptor Binding Free Energy by 4D-QSAR Analysis: Application to a Set of Glucose Analogue Inhibitors of Glycogen Phosphorylase

Abstract

A set of 47 glucose analogue inhibitors of glycogen phosphorylase was investigated using 4D-QSAR analysis. A single significant 4D-QSAR model, having no outliers, was found as a function of alignment and conformational sampling. This 4D-QSAR model consists of six grid cell occupancy descriptors which defines the thermodynamic averaged spatial pharmacophore for this set of analogues. The 4D-QSAR model was validated by aligning it upon the crystal structures of glycogen phosphorylase with some bound inhibitors of the training set. Validation of the 4D-QSAR model was realized by establishing the consistency of the types and locations of the grid cell occupancy descriptors relative to the binding interaction sites of the crystal complex. The loss in binding free energy, due to loss in inhibitor conformational entropy upon binding to the enzyme, was computed and found to be in the 0−2 kcal/mol range for these inhibitors. The “active” conformation of each analogue was also postulated from the 4D-QSAR model.