In this study, we adopt Rathi et al. DNN model to calculate the charges for an ESP surface. This model was proved to be well fitted to DFT-level ESP surfaces and much faster than standard QM calculations. The ESP value on the surface was calculated using Coulomb!s equation and we additionally applied a distance dependent relative permittivity. Additional details of the ESP calculation can be found in Supporting InformationFor EC score calculation, we take the notion that total EC score is the averaging sum of local ECs. A well-defined local EC should reflect the notion that the ESP pairs of proteins and ligands at a small area are scored better if they are similar in value but opposite in sign. However, the traditional methods to calculate EC (e.g. Pearson!s R correlation or Spearman!s Rho rank correlation coefficients) do not meet this criteria. Also, we expected that small value ESP pairs contribute much less to the total activity. That is reasonable because small value ESP pairs means weak interaction. Thus, we heuristically proposed equation (2) for small ESP pairs' EC calculation which approach value zero.