As a baseline comparison of DUck with other fast methods, we optimized rDock scores and performed single-point MM/GBSA calculations. For the rDock scores, the ligand coordinates (i.e., the crystal structures for HSP90α and BACE1 and the tethered docking poses for CDK2) were minimized with the minimize.prm rDock protocol. Then SCORE.INTER was recorded as the docking descriptor. In parallel, the original poses were transformed into the Maestro format using the structcat command from the Schrodinger suite. The MM/GBSA calculations were performed using the Prime package in the Schrödinger Prime Suite, accounting for the ligand strain. The reported ΔGbind was recorded as the MM/GBSA descriptor. The differences in SCORE.INTER and ΔGbind were used to predict activity cliffs, in the same way as ΔGQB in DUck.