Overall, the HSP90α data set consisted of 93 HSP90α inhibitors (13 binding to the loop confirmation and 80 to the helical conformation), resulting in 207 pairs (18 activity cliffs and 89 non-cliff pairs). The CDK2 series consisted of 497 active inhibitors, forming 1164 pairs (121 activity cliffs and 1043 non-cliff pairs), with the series being very evenly populated. The 50 BACE-1 inhibitors formed 82 pairs with only three activity cliffs. Dynamic Undocking. The DUck standard pipeline was used for each protein-ligand complex. Proteins were prepared using MOE-2016 by correcting missing side chains, fixing protonation states, and adding terminal capping. The chunk selection was done using the residues within 8 Å from the receptor's atom involved in the hydrogen bond, and then manually trimming out the external residues that do not interact with the binding pocket. Ligand parameters were obtained from the Pfrosst forcefield, 1 and the partial charges were calculated with AM1-BCC. To account for the plasticity of the HSP90α binding site, receptor coordinates were extracted from different PDB structures: 2VCI, 5J9X, 5OD7, and 5OCI for resorcinol loopbinders, resorcinol helix-binders, quinazolines, and imidazoles, respectively. In the case of CDK2, the PDB entry 1H1S was used to generate the protein conformation, and the H-bond to study was formed with the backbone of L83 in the hinge. The 1TQF PDB entry was used to model the BACE1 structure where H-bonds with the backbone oxygen of G291 were studied. Each ligand was submitted to a DUck run with 100 cycles of steered molecular dynamics. All simulations were performed with the AMBER16 CUDA version of PME. Quasi-bound free energies (ΔGQB) were calculated using Jarzynski's equality. Jarzynski's equality (equation 1) relates the exponential average of works, obtained from simulating a non-equilibrium process repeatedly, directly with the ΔG, where kβ corresponds to the Boltzmann constant, and T to the simulation temperature: