Fragment-Based Drug Discovery: Advancing Fragments in the Absence of Crystal Structures

Fragment-based drug discovery typically requires an interplay between screening methods, structural methods, and medicinal chemistry. X-ray crystallography is generally the method of choice to obtain three-dimensional structures of the bound ligand/protein complex, but this can sometimes be difficult, particularly for early, low-affinity fragment hits. In this Perspective, we discuss strategies to advance and evolve fragments in the absence of crystal structures of protein-fragment complexes, although the structure of the unliganded protein may be available. The strategies can involve other structural techniques, such as NMR spectroscopy, molecular modeling, or a variety of chemical approaches. Often, these strategies are aimed at guiding evolution of initial fragment hits to a stage where crystal structures can be obtained for further structure-based optimization. Fragment-based drug discovery (FBDD) generally relies on crystal structures of fragments bound to the target protein. Erlanson, Davis, and Jahnke review strategies and approaches for successful FBDD in cases when these crystal structures are not available