Drug-target residence time, the length of time for which a small molecule stays bound to its receptor target, has increasingly become a key property for optimization in drug discovery programs. However, its in silico prediction has proven difficult. Here we describe a method, using atomistic ensemble-based steered molecular dynamics (SMD), to observe the dissociation of ligands from their target G protein-coupled receptor in a time scale suitable for drug discovery. These dissociation simulations accurately, precisely, and reproducibly identify ligand-residue interactions and quantify the change in ligand energy values for both protein and water. The method has been applied to 17 ligands of the A2A adenosine receptor, all with published experimental kinetic binding data. The residues that interact with the ligand as it dissociates are known experimentally to have an effect on binding affinities and residence times. There is a good correlation ( R2 = 0.79) between the computationally calculated change in water-ligand interaction energy and experimentally determined residence time. Our results indicate that ensemble-based SMD is a rapid, novel, and accurate semi-empirical method for the determination of drug-target relative residence time.