Fragment-Based Approaches

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.

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