Prediction of ligand-receptor binding thermodynamics by free energy force field three-dimensional quantitative structure-activity relationship analysis: applications to a set of glucose analogue inhibitors of glycogen phosphorylase.

Glucose analogue inhibitors of glycogen phosphorylase, GP, may be of clinical interest in the regulation of glycogen metabolism in diabetes. The receptor geometry of glycogen phosphorylase b, GPb, is available for structure-based design and also for the evaluation of the thermodynamics of ligand-receptor binding. Free energy force field (FEFF) 3D-QSAR analysis was used to construct ligand-receptor binding models. FEFF terms involved in binding are represented by a modified first-generation AMBER force field combined with a hydration shell solvation model. The FEFF terms are then treated as independent variables in the development of 3D-QSAR models by correlating these energy terms with experimental binding energies for a training set of inhibitors. The genetic function approximation, employing both multiple linear regression and partial least squares regression data fitting, was used to develop the FEFF 3D-QSAR models for the binding process and to scale the free energy force field for this particular ligand-receptor system. The significant FEFF energy terms in the resulting 3D-QSAR models include the intramolecular vacuum energy of the unbound ligand, the intermolecular ligand-receptor van der Waals interaction energy, and the van der Waals energy of the bound ligand. Other terms, such as the change in the stretching energy of the receptor on binding, change in the solvation energy of the system on binding, and the change in the solvation energy of the ligand on binding are also found in the set of significant FEFF 3D-QSAR models. Overall, the binding of this class of ligands to GPb is largely characterized by how well the ligand can sterically fit into the active site of the enzyme. The FEFF 3D-QSAR models can be used to estimate the binding free energy of any new analogue in substituted glucose series prior to synthesis and testing.