Ligand specificity, privileged substructures and protein druggability from fragment-based screening

Fragment-based screening has now become an established method for the generation of lead molecules against therapeutic targets. Fragment molecules are simple, low molecular-weight compounds with few chemical functionalities. These characteristics lead to high hit rates for fragment screening as compared to the more classical High-Throughput Screening of drug-like molecules and raise the question of the specificity of fragment molecules. This review analyzes recent outcomes of fragment screenings published in the literature, showing that the specificity of the fragments can be related to their structures and physico-chemical properties. We also discuss both the concept of privileged fragment scaffolds and the role of fragment-based screening in predicting protein druggability, highlighted by recent publications in the field.

► Fragment-based screening to study ligand specificity at weak affinity. ► Fragment-based screening to assess the protein druggability. ► Fragment-based screening to study privileged substructures.