It has been previously reported that using MM-PBSA long MD simulations seem not to result in better predictions and short MD simulations can be adequate in calculating binding affinities . In order to achieve a higher precision it has been suggested to run many short independent simulations (produced by e.g. replicate sampling) instead of a single long one, which should avoid underestimation of the uncertainty . Additionally, if one is only interested in the relative order of binding affinities, the ranking of compounds with similar structures and binding modes, the entropy contribution to the binding free energy can be omitted, which is often recommended as it reduces the computational cost and avoids adding an additional non-negligible error margin. It has been found that MM-PB/GBSA performances generally vary with the tested system and also depend on the used force fieldand the solute dielectric constant .