In CACHE #2, computational teams were asked to find molecules that target a pocket occupied by fragments in the PDB, a common challenge successfully met by the COVID moonshot initiative that targeted the SARS-CoV-2 protease , which could also be undertaken for other targets. In our challenge, the crystallized fragments were weak and had no measurable binding affinity by SPR (data not shown). Only eight out of 23 computational teams explicitly used the bound fragments in their selection strategy, and two of these were among the most successful workflows (Figures and). This shows that rationally optimizing crystallized fragments remains a challenging exercise that requires further developments before it can be reliably applied. Considering the multitude of targets with bound fragments in the PDB, including those taken to fragment screening by crystallography , technological development in this area of computational design could be impactful.