Ligands occupying 1 subpocket. Additionally, 127 ligands (5%) target only one subpocket and were left unfragmented during the fragmentation procedure. Since this study focuses on ligands covering the AP subpocket, all these unfragmented ligands are located in AP. They have an average number of 15 heavy atoms, which is higher than the average over all AP fragments (11 heavy atoms). As shown in Figure .B-D, these molecules represent either (i) small fragment-like molecules or (ii) large rigid molecules that contain a large fraction of rings, which are difficult to split for fragmentation most algorithms. An example for the former group (i) is the series of halogenated pyrazoles that stem from a fragment-based approach for druggability assessment and hit generation, 47 see Figure .B1-B8. The latter group (ii) contains complete drug-like molecules that either could not be divided because none of the BRICS rules applied or they had a potential BRICS cleavage bond in the initial fragmentation step, which was not broken because the two potential fragments were located in the same subpocket. Furthermore, there are rigid molecules that only contain fused rings with small decorations and, thus, do not apply to any fragmentation approach (such as quinalizarin, a CK2 inhibitor, and derivatives, see Figure .C1-C2). An example of a molecule that could not be fragmented by BRICS is the co-crystallized ligand HK4 (CHEMBL248396, ). The two ring moieties clearly cover distinct subpockets (AP and GA), but could not be assigned to them since no rule exists that allows to split next to a triple bond between two carbon atoms.