An extensive evaluation of the linear interaction energy (LIE) method for the prediction of binding affinity of docked compounds has been performed, with an emphasis on its applicability in lead optimization. An automated setup is presented, which allows for the use of the method in an industrial setting. Calculations are performed for four realistic examples, retinoic acid receptor γ, matrix metalloprotease 3, estrogen receptor α, and dihydrofolate reductase, focusing on different aspects of the procedure. The obtained LIE models are evaluated in terms of the root-mean-square (RMS) errors from experimental binding free energies and the ability to rank compounds appropriately. The results are compared to the best empirical scoring function, selected from a set of 10 scoring functions. In all cases, good LIE models can be obtained in terms of free-energy RMS errors, although reasonable ranking of the ligands of dihydrofolate reductase proves difficult for both the LIE method and scoring functions. For the other proteins, the LIE model results in better predictions than the best performing scoring function. These results indicate that the LIE approach, as a tool to evaluate docking results, can be a valuable asset in computational lead optimization programs. © 2006 American Chemical Society.