The free ligand was solvated with TIP3P water and 150 mM NaCl in a periodic box of side length 40 Å. 50000 steps of minimisation were performed using PMEMD. Equilibration in the N V T ensemble was performed using PMEMD (5 ps with all non-solvent atoms restrained and heating from 0 to 298 K, followed by 50 ps with no restraints), followed by equilibration in the N P T ensemble with PMEMD.CUDA (1 atm and 298 K with restraints on non-solvent heavy atoms for 200 ps followed by 2 ns with no restraints). A Langevin thermostat and Berendsen barostat were used for the relevant equilibration steps. All alchemical simulations were performed using the software SOMD, available within Sire (version 2022.2.0). SOMD was modified to allow the use of Boresch restraints, the scaling of restraints with λ 5 , and the simultaneous use of different restraints. The code implementing Boresch restraints has been integrated into the main branch of Sire. An