We furthermore compared ESP-Sim scores to similarities obtained via the state-of-the-art tool EON for about 450 fragments generated by DeepFMPO for various partial charge distributions. We find a strong correlation, with Spearman correlation coefficient of about 0.8. A detailed analysis is given in the Supporting Information. In addition, we assessed the ability of ESP-Sim scores to identify potential ligands to protein targets. We compared the performance of ESP-Sim electrostatic and shape similarities to a set of re-scoring functions on the dopamine D4 receptor, for which experimental data on active and inactive compounds is known. We furthermore benchmarked ESP-Sim on the 102 DUD-E targets and compare its performance against a variety of ligand-based approaches. For both comparisons, we find that ESP-Sim electrostatic and shape similarities perform very well. Details on these benchmarks are given in the Supporting Information.