FBLD

FBLD, or fragment-based lead discovery, is a drug discovery approach that uses small, low-molecular-weight chemical fragments to identify starting points for lead compounds targeting a biological molecule such as a protein. Fragments typically have molecular weights around 150–250 Da and bind with high ligand efficiency, enabling efficient exploration of chemical space with smaller libraries than traditional high-throughput screening.

Screening is followed by validation using orthogonal biophysical methods such as NMR spectroscopy, X-ray crystallography, or surface plasmon resonance. Structural information guides optimization by fragment growing, merging, or linking to increase potency while maintaining favorable properties. The process is iterative, with cycles of design, synthesis, and testing to produce a lead compound.

Advantages include efficient coverage of chemical space, access to novel scaffolds, and good ligand efficiency that can translate into favorable drug-like properties. FBLD can be more efficient than traditional screening for certain targets and is especially useful for targets with shallow binding surfaces or limited existing chemotypes.

Challenges involve reliance on sensitive biophysical methods and high-quality target structures, complexity in linking or merging fragments into drug-like molecules, and the risk of rapid increases in molecular weight during optimization. Success depends on thoughtful fragment library design, access to structural information, and robust medicinal chemistry capabilities. The approach gained prominence in the late 1990s and early 2000s and has been adopted by multiple pharmaceutical companies, including early adopters like Astex Therapeutics, as a complementary or alternative path to traditional screening strategies.