As an alternative to RBFE methods, we propose that absolute binding free energies (ABFE) could instead be used to directly investigate fragment affinities. Despite larger computational costs, ABFEs offer a direct solution to the above described limitations of RBFEs by directly calculating the absolute free energy of binding for each individual ligand, and not requiring a transformation to another chemical entity. Previous works have shown ABFEs to offer highly accurate estimates of binding free energies across a variety of target systems, although often at increased computational costs . Indeed the idea of using ABFEs in fragment binding is not a novel one, and we note several other investigations employing such methods for fragment-sized molecules . That being said these have been mostly limited in scope and to our knowledge there have yet to be any large scale analyses of the applicability of ABFEs to the FBDD process.