Estimation of the binding free energy differences between protein ligands by the FEP/TI method

Abstract

Binding free energy ΔGbind of a ligand to the target protein is a physicochemical quantity which closely relates to a drug activity, and prediction of ΔGbind with accuracy leads to an efficient drug design. As a method to calculate ΔΔGbind, difference of ΔGbind between two ligands, FEP (free energy perturbation) and TI (thermodynamic integration) methods are well known. Theoretically, application of these methods are limited to the system where an energy difference is small, ~2 kcal/mol. Recently, Jorgensen et al. have applied these methods to a lead optimization study of HIV reverse transcriptase inhibitors, and succeeded in obtaining a qualitative relationship between the predicted and experimental values. However, it is desirable to establish an appropriate calculation procedure of these methods which reproduces experimental ΔΔGbind quantitatively. In this study, we applied the FEP/TI methods to the FXa (activated blood coagulation factor X) inhibitors, where one hydrogen atom on an inhibitor molecule was replaced with a chlorine atom. Several calculation procedures have been tested.