For the rest of the study, three other data sets were prepared for ligands binding to HSP90α, CDK2, or BACE1 proteins, to detect activity cliffs in those data sets. HSP90α ligands, their binding mode, and the receptor conformation they bind to were shared generously by Kokh D. The data sets for CDK2 and BACE1 were compiled by extracting the ligands from crystal structures in the PDB. The CDK2 data set was expanded using compounds from ChEMBL with a known activity. We generated the 3D structure of ChEMBL compounds and prepared them using LigPrep of the Schrödinger suite. Their binding poses were obtained with tethered docking calculations using rDock. We employed the maximum common substructure with the most similar compound from the PDB to select the tethered atoms. This was done assuming that small structural differences between the reference and docked compounds would not cause major shifts in binding mode. Nonetheless, those ligands that showed drastic changes in the binding mode during the MD sampling were removed from the series. The ligands with a disruption of the binding mode adopt a suboptimal position where the key hydrogen bond is very likely to dissociate. Therefore, the first indicator of a shift in the binding mode is an abnormally low WQB. Finally, the ligands were visually inspected to correct wrong protonation states and other artifacts from the preparation process.