fragmentbased

Fragment-based (often referred to as fragment-based drug discovery or FBDD) is a strategy in medicinal chemistry in which small, low-molecular-weight chemical fragments are screened for binding to a biological target. These fragments, typically with molecular weight under 300 Da and high ligand efficiency, bind with weak affinity but offer efficient coverage of chemical space. Hits are then elaborated through structure-guided optimization to produce higher-affinity, drug-like compounds.

Fragment libraries are designed to maximize structural diversity and include diverse heteroatoms; screening methods include biophysical techniques such as nuclear magnetic resonance spectroscopy, X-ray crystallography, surface plasmon resonance, and differential scanning fluorimetry. Because fragments bind weakly, hits must be validated and their binding modes confirmed, often by co-crystal structures or NMR.

Optimization strategies include fragment growing (adding atoms to increase affinity), fragment merging (combining two bound fragments), and fragment linking (connecting fragments that bind in proximity). This process is iterative and typically involves medicinal chemistry, structural biology, and pharmacokinetic assessment.

Advantages include efficient exploration of chemical space with smaller libraries, higher hit rates per molecule, and the ability to discover novel binding modes. Limitations include the need for sensitive biophysical instrumentation, favorable target properties, potential developability challenges, and longer optimization timelines in some cases.

Fragment-based approaches have contributed to numerous drug discovery programs across targets such as kinases and proteases and remain a common component of modern drug discovery, often complementing high-throughput screening and structure-based design. The term covers both the strategy and the associated practices used to identify fragment hits and progress them to lead candidates.