3.2. Large Inhibitor Data Set. The T4-lysozyme data set was a useful starting point to establish best practices for large systems with small ligands. Good accuracy for very small ligands is important in order to meet the requirements of fragment-based approaches to drug design and discovery, 133-138 which search for "hits" based on small-molecule probes rather than larger ligand models that resemble existing drugs. This strategy has been suggested as a salve to remedy a slow drift towards drug candidates with larger and larger molecular weight, 139 a trend that has been blamed for increased attrition rates in clinical trials. That said, with an eye towards computational investigation of existing drug molecules, or structure-based drug design, it is important to understand how fragmentation protocols fare for much larger ligands, epitomized by those in Fig. . Each of these ligands is larger than 40 atoms and there is also more variety in the enzymatic targets as compared to the T4lysozyme data set.