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 clinic al interest in the regulation of glycogen metabolism in diabetes. The recep tor geometry of glycogen phosphorylase b, GPb, is available for structure-b ased design and also for the evaluation of the thermodynamics of ligand-rec eptor binding. Free energy force field (FEFF) 3D-QSAR analysis was used to construct ligand-receptor binding models. FEFF terms involved in binding ar e represented by a modified first-generation AMBER force field combined wit h a hydration shell solvation model. The FEFF terms are then treated as ind ependent variables in the development of 3D-QSAR;models by correlating thes e energy terms with experimental binding energies for a training set of inh ibitors. 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 fr ee energy force field for this particular ligand-receptor system. The signi ficant FEFF energy terms in the resulting 3D-QSAR models include the intram olecular vacuum energy of the unbound ligand, the intermolecular ligand-rec eptor 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 b inding, 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 bin ding of this class of ligands to GPb is largely characterized by how well t he ligand can sterically fit into the active site of the enzyme. The FEFF 3 D-QSAR models can be used to estimate the binding free energy of any new an alogue in substituted glucose series prior to synthesis and testing.