Structure-based drug discovery methods are generally based on predicting the binding affinity of a ligand to a protein. Ruiz-Carmona et al. introduce a novel computational procedure termed dynamic undocking (DUck), which evaluates the structural stability of protein–ligand complexes. DUck calculates the work needed to break a key native contact and reach a quasi-bound state. In test systems, active compounds were structurally stable and presented higher quasi-bound values than inactive ones. DUck is orthogonal to existing virtual screening methods: in a fragment screening against HSP70, DUck identified novel chemotypes and had a hit rate of 38%.