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

Abstract

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.

Docking flexible ligands in proteins with a solvent exposure- and distance-dependent dielectric function

“…Combining the AMBER force field with the hydration shell model yielded correlation of the experimental and predicted binding energy in a series of 23 glucose analogue inhibitors of glycogen phosphorylase [54]. In our approach, the solvent exposure-dependent component of the SEDDD function weakens interactions at the protein surface thus accounting for the dehydration energy.…”

Human protein tyrosine phosphatase 1B inhibitors: QSAR by genetic function approximation

“…GFA has been applied to a set of ellipticine analogues for different types of anticancer activities [7]. Recently, GFA was used for binding affinity predictions of ligands using free energy force field descriptor terms as in the case of inhibitors of glycogen phosphorylase [8] and peptidomimetic renin inhibitors [9,10]. GFA has also been used for the QSAR analysis of steroids, dopamine b-hydroxylase inhibitors [11] and anticancer agents [12].…”

Simulation‐Based Predictions of Binding Affinities of Matrix Metalloproteinase Inhibitors

“…VALIDATE [49], one of the most elaborate methods based on single structures considers, in addition to electrostatic and van der Waals interactions, the number of rotatable bonds frozen in the receptor-ligand interaction, lipophilicity of the ligand, surface complementarity, and ligand strain energy. The Free Energy Force Field approach [50,51], although using an MD simulation, finally selects single configurations to calculate free energy contributions that are weighted to fit experimental data. Conformational entropy is treated via group contributions and hydration through a specific solvation model.…”