Fragment-based drug design (FBDD) is an approach to lead discovery that screens small, low-molecular-weight compounds (fragments) against a target protein. Fragment libraries are typically 100–300 Da in size, much smaller than the compounds in traditional HTS libraries. Fragments bind weakly, with affinities in the micromolar to millimolar range, but they achieve high ligand efficiency by forming high-quality interactions with the target.

Fragment screening identifies simple chemical motifs that bind to the target, which are then elaborated into larger, higher-affinity compounds through structure-guided medicinal chemistry. This approach covers chemical space more efficiently than HTS because fewer fragments are needed to sample the same diversity.

Fragment libraries are designed for structural diversity, aqueous solubility, and suitability for X-ray crystallography. Typical libraries contain 1,000–3,000 fragments. Screening methods must detect weak binding and include NMR spectroscopy, surface plasmon resonance, thermal shift assays, and mass spectrometry. X-ray crystallography of fragment-soaked crystals provides detailed binding mode information.

Hit-to-lead strategies for fragments include fragment linking, where two fragments binding to adjacent sites are connected by a linker, fragment merging that combines features from multiple fragments, and fragment elaboration that grows the fragment into adjacent binding pockets. Ligand efficiency metrics including binding efficiency index and lipophilic efficiency guide optimization.