To do so, we took the ratio of numerical optimization criteria as explained in Eqs. 8, 16, and 15. We randomly selected ligand sets from the Protein-Ligand-Benchmark set: Tyk2, Cdk2, Tnks2, Ptp1b, and Pfkfb3 . Ligand structure files are accessible . Efficiencies were calculated over the whole ligand sets without clustering, except for Tnks2. For Tnks2, LOMAP did not output a fully connected graph. For consistency we used the ligands corresponding to the larger design output by LOMAP for efficiency calculations. HiMap calculated the reference ligand chosen for optimization and as the central hub for radial designs (Software Methods).