Data reduction. The full fragment library contains 7,486 fragments. In order to reduce the combinatorial library size and run time, a diverse subset of fragments was chosen. (i) All fragments that are not suitable for recombination were removed, i.e. duplicates, fragments in pool X, fragments without dummy atoms (unfragmented ligands), and fragments with dummy atoms only connecting to pool X. Furthermore, only fragments complying with the rule of three, 31 a filter for fragment-likeness, and hinge-like AP fragments were kept. The latter filter checks for at least one hydrogen bond donor or acceptor in the AP fragment, together with at least one aliphatic or aromatic ring. The filtering steps in (i) result in 2,029 fragments. (ii) Per subpocket, a diverse set of fragments was selected for recombination to avoid enumerating highly similar fragments. The Butina algorithm 30 was applied to cluster each subpocket's filtered fragments using topological RDKit molecular fingerprints and a distance threshold of 0.6. Per cluster, the most common fragments were selected. The larger the cluster the more fragments were chosen (one fragment per 10 cluster members, whereby clusters with less than 10 fragments are represented with one fragment). The final reduced fragment library consists of 624 fragments (AP: 145, FP: 192, SE: 140, GA: 93, B1: 24, and B2: 30).