Our results evidence that ΔGQB, despite being a local property of protein-ligand complexes, can be used to confidently predict ΔΔGbind a global property of the system. But this is only true for ligands dissociating with: a) a steep barrier (early transition state), and b) in a single step (no metastable states). ΔGQB provides the barrier steepness, but the second condition is more difficult to predict. We suggest a simple protocol, using a reference ligand per chemical series. If the ligand's ΔGQB is high, we advise performing molecular dynamics studies to assess the dissociation mechanism. Here, τRAMD quickly showed a clear signal to distinguish between ligands following a one-step dissociation and those with more complex pathways; however other meta-dynamics approaches can also be used. Using this approach, we have successfully predicted activity cliff formation in three congeneric ligand data sets of different proteins. Activity cliffs remain a major challenge for virtual screening. On the one hand, while alchemical free energy calculating methods have shown promising results (see and our TI results at the beginning of this study), they are too costly to be applied in a high-throughput fashion. On the other hand, data-driven approaches struggle due to the non-continuous relationship between binding affinity and chemical space. In this scenario, DUck suggests a middle ground where reliable, albeit semiquantitative, predictions can be made in a high-throughput way, offering an ideal solution for systems within the scope of the method. It is noteworthy that in some cases, as we have shown for HSP90α, ΔGQB can even be used for rank-ordering within congeneric series. Naturally, one can increase the quality of the prediction by using less drastic approximations (e.g. full system representation, slower dissociation, careful selection of the reaction coordinate). In fact, one important conclusion from this work is that theoretically rigorous path-sampling approaches have a great advantage when the system under investigation dissociates in a single step, with an early transition state. This appears to be a relatively frequent situation, and one that structure-based methods should take advantage of.