Despite the positive results displayed here, it is important to make clear that in many ways this benchmark only tackles a simplified set of tasks in the FBDD process and that several challenges remain ahead in validating and using absolute binding free energies. Of particular note, this dataset solely looked at cases where most binding poses were known and as a consequence were likely to not include ligands occupying more than one binding pose significantly contributing to the total free energy. Thus, our use of orientational restraints in this study could be justified. However there are FBDD cases where accounting for multiple binding sites either through less restrictive restraints, such as center of mass restraints 100,108- 111 or through enhanced sampling means (e.g. NCMC 112 or metadynamics 113 ), will be required.