The second class of approaches uses rigorous dynamics reweighting schemes which can reconstruct the original dynamics of the system. Examples include methods based on Multistate Markov State Models, Weighted Ensemble, Milestoning, Weighted-ensemble Milestoning, and Markovian Milestoning with Voronoi Tesselations. These approaches are general, conserve the relationship between different timescales occurring in the system, and provide an absolute estimate of the residence times. Nevertheless, they are computationally intensive (averaging a few microseconds of simulation time per ligand ) and hence mostly unsuitable for driving drug discovery design cycles where considerable numbers of ligands need to be profiled in a limited time. Therefore, in this context, using an artificial biasing potential is For each system, we retained all crystallographic water molecules in the binding site. We then used Epik and PROPKA to assign the ligand and protein protonation states and optimize the hydrogen-bond network for every complex. followed by a minimization with positional restraints on heavy atoms.