Fragment-based ligand design is a novel concept for lead identification in drug discovery. Rather than screening for lead- or drug-sized, fully assembled inhibitors as in high-throughput screening, small molecular fragments are identified that bind the molecular target in a weak but validated manner. One of several strategies is then followed to optimize the initial weak fragments into a high-affinity ligand. In fragment-based drug discovery, the lead compound is thus built piece-by-piece, in a modular way. Most optimization strategies rely on structural information. Fragment-based screening can therefore be viewed as the marriage between screening and structure-based drug design. This review describes the concept of fragment-based drug discovery and discusses its advantages and requirements. Technologies for screening and structure determination are discussed, and some key examples for various technologies and optimization strategies are presented.

Helicases form an attractive protein family for drug discovery because they are involved in various human diseases. In this report, we show that it is possible to inhibit both the ATPase and the helicase activities of a DNA helicase with dibenzothiepins that bind at its nucleic acid binding site. These results suggest a drug discovery strategy to inhibit DNA helicases.