Prediction of ligand-receptor binding thermodynamics by free energy force field (FEFF) 3D-QSAR analysis: application to a set of peptidometic renin inhibitors.

A methodology is presented and applied in which the accurate estimation of ligand-receptor binding thermodynamics is achieved by formulating the calculation as a QSAR problem. When the receptor geometry is known, the free energy force field (FEFF) ligand-receptor binding energy terms can be calculated and used as independent variables in constructing FEFF 3D-QSARs. The FEFF 3D-QSAR analysis of a series of transition state inhibitors of renin was carried out. From a statistical analysis of the free energy contributions to the binding process, FEFF 3D-QSARs were constructed that reveal the change in solvation free energy upon binding and the intramolecular vacuum internal energy of the ligand in the unbound state are the most significant FEFF terms in determining the binding free energy, delta G. Other terms, such as ligand stretching, bending, and torsion energy changes, the intermolecular van der Waals interaction energy, and change in ligand conformational entropy upon binding, are also found to make significant contributions in some FEFF 3D-QSAR delta G models and in delta H and delta S binding models. Overall, a relatively small number of the thermodynamic contributions to the ligand-receptor binding process dominates the thermodynamics of binding in a given model.