Both ligand representation and their selection protocol are essential components for the efficiency and accuracy of the active learning protocol in Figure . Firstly, we evaluated the effectiveness of different ligand representations by encoding the ligand library with diverse 2D and 3D ligand descriptors (2D_3D), ligand-protein interaction fingerprints (PLEC), interaction energies from molecular mechanics force fields (MDenerg, MDenerg_LR) and gridbased ligand representations (atom_hot and atom_hot_surf) (Fig. top row). These ligand representations are described in more detail in the Methods section.