We evaluated the power of our ensemble-docking protocol to enrich known Abl inhibitors over an in-house curated library of negative examples including known non-binders and randomly selected molecules. We compared a conformational ensemble (n=16, RMSF=2.7Å) generated using our protocol to a conformational ensemble (n=16, RMSF=2.4Å) derived from a Markov-state model (MSM) based on extensive molecular dynamics simulations . We also calculated the enrichment factor from the smina rank of docked poses to the (relaxed) crystal structure. We then compared the chemical diversity of active top compounds docked to single receptor conformations to those using the rosetta-ensemble. We selected the 1% top-ranked compounds for each method. These 90 compounds would approximately fill a 96-well plate used for experimental validation in a vHTS screen. We then selected all active compounds among the top 1% for the single receptor conformation/smina ranking (31 compounds) and the rosettaensemble/AtomNet PoseRanker (59 compounds) method. We excluded two compounds that ranked within the top 90 in both methods, since we are primarily interested in examining their differences. A t-SNE 63 projection of a principal components analysis computed from their ECFP4 fingerprints suggests that the rosetta ensemble is slightly more diverse compared to the single conformation compounds (Fig ). Towards the lower left corner of the t-SNE projection, smina uncovers exceedingly fewer compounds. In the lower right corner, the first t-SNE coordinate separates a cluster of compounds at 't-SNE 1' > 2 that were enriched nearly exclusively in the ensemble. These compounds are all analogs of Ponatinib (Fig 6C ), notably sharing the ethynyl linker to a imidazol-1,2-pyridazine-like hinge region of the compound. AtomNet PoseRanker identified the most hits in this cluster against receptor conformations 13 and 16. Altogether, two out of 25 hits in this cluster were identified from docking to a single receptor (blue circle, using smina, and another from AtomNet PoseRanker (Fig 6D )). Among all top 1% of compounds in both docking methods, only two Ponatinib analogs were identified using smina ranking.