Fragment-based drug design is now recognized as an attractive method to design novel potent molecules (1-3). The first step of the process consists of screening libraries of fragments, the physicochemical properties of which are consistent with the rule of three (4). Owing to their low chemical complexity, the fragments usually bind the protein target with low affinity (high mM), but exhibit high ligand efficiency (DG of binding per heavy atom) as compared with larger elaborated drug-like ligands (5). The fragments selected for follow-up are then optimized by addition of chemical moieties or linked together with the aim of obtaining a highly potent drug or inhibitor (6).
In spite of their low complexity leading to weak affinity for their macromolecule target (KD > 100 µM), fragments were shown to bind protein hot spots, focal points where binding energy is concentrated (7), independent of their structure and affinity (8-9). Interestingly, hit rates in fragment-based screening was reported to be correlated with the protein ability to bind drug-like ligands with high affinity, which led to propose fragment-based screening results as a tool to assess protein druggability (8-12).
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