We present a new computational strategy for calculating the absolute binding free energy for protein ligand association in the context of atomistic simulation in explicit solvent. The method is based on an appropriate definition of a solute tempering scheme enforced via Hamilton replica exchange method (HREM). The definition of "solute" includes both the ligand and the active site, with the remainder of the systems defined as "solvent". The hydrophilicity of the solute and the solute torsional plus nonbonded intrasolute interactions are increased and decreased, respectively, along the replica progression, thus favoring the extrusion of the drug form the active site in the scaled states of the generalized ensemble. The proposed technique, named "Energy Driven Undocking" (EDU-HREM), completely bypasses the need for defining and/or identifying the relevant reaction coordinates in a ligand receptor interactions and allows the calculation of the absolute binding free energy in one single generalized simulation of the drug-receptor system. The methodology is applied, with encouraging results, to the calculation of the absolute binding free energy of some FK506-related ligands of the peptidyl prolyl cis-trans isomerase protein (FKBP12) with known dissociation constants. Aspects of the binding/inhibition mechanism in FKBP12 are also analyzed and discussed.