The various ligands used in this study are shown in Figures , and S15. A prerequisite for GCNCMC simulations is to calculate the excess chemical potential, µ ′ sol , for the ligand in question. These values were calculated using a basic hydration free energy FEP calculation. The molecule of interest is placed in the center of a 40x40x40 Å box containing 2135 water molecules. The system is then equilibrated for 3 ns in the NPT ensemble at 298 K. The ligand is then decoupled from the box over 30 lambda values with the first 10 turning off the electrostatics and the final 20 the Lennard-Jones interactions. At each lambda value, the system is equilibrated for 0.5 ns before being run for a further 2 ns with potential energy samples collected every 1000 timesteps. Free energies were calculated using the multistate Bennett acceptance ratio (MBAR) as implemented in pymbar. Generally, four repeats per ligand are performed with the mean average taken forward. A comparison of the calculated µ ′ sol for ligands with experimental hydration free energies can be found in the SI.