Advantages of screening low molecular weight fragment based libraries over traditional higher molecular weight chemical libraries are several.   These include:
* More hydrophilic hits in which hydrogen bonding is more likely to contribute to affinity (enthalpically driven binding).  It is generally much easier to increase affinity by adding hydrophobic groups (entropically driven binding); starting with a hydrophilic ligand increases the chances that the final optimized ligand will not be too hydrophobic (log P  < 5).
* Higher ligand efficiency so that the final optimized ligand will more likely be relatively low in molecular weight (MW < 500).
* Since two to three fragments in theory can be combined to form an optimized ligand, screening a fragment library of N compounds is equivalent to screening N - N compounds in a traditional library.
* Fragments are less likely to contain sterically blocking groups that interfere with an otherwise favorable ligand-protein interaction, increasing the combinatorial advantage of a fragment library even further.