When ligands are designed starting from fragment hits (rather than docking a subset of compounds in a dataset), the protein-ligand complex data available from initial fragment hit structures are often still not utilised until after initial enumeration. Approaches are usually synthon-based, where molecules are broken down into components and then new molecules are designed by combination of components from multiple input ligands. Examples include BRICS decomposition and AutoGrow4 . Neither of these methods consider any 3D structural information from the protein or ligand in the initial enumeration step. Some methods do consider some spatial information from the protein. DeLinker is an example of a method which takes advantage of the 3D structural information of known ligands by identifying connection vectors between ligands and generating molecules that will fit into that 3D ligand space. However, it is still unaware of the protein environment around the ligands it is designing from. GANDI takes protein coordinates into consideration to filter out potential clashes , whilst designing linkers in a similar manner to DeLinker. DEVELOP takes this a step further by encoding both protein and ligand conformation into both connectivity (via a graph neural network) and coordinate information (through a voxel occupancy map) in its training to encode pharmacophoric features that can be used to predict new molecules for a protein target not in its training dataset . STRIFE improves upon the predictions made by DEVELOP by also performing docking constrained to hotspot maps to better assess the products after a coarse-grain and a finegrain step . None of the methods discussed thus far consider the 3D conformation of overlapping hits. An algorithm that stands out in this respect is BREED , implemented within Maestro in the Schrödinger suite, this algorithm joins fragments hits by hybridizing upon spatially overlapping bonds, thus obeying the conformation of the hits. However, it's a commercial product. In practice, in most situations, fragment merging is most often done by eye .