Development of potent inhibitors by fragment-linking strategies

Fragment-based drug discovery (FBDD) is a method of identifying small molecule hits that can be elaborated rationally through fragment growing, merging and linking, to afford high-affinity ligands for biological targets. Despite the promised theoretical potential of fragment linking, examples are still surprisingly sparse and remain overshadowed by the successes of fragment growing. The aim of this review was to outline a number of key examples of fragment-linking strategies and discuss their strengths and limitations. Structure-based approaches including X-ray crystallography and in silico methods of fragment optimization are discussed, as well as fragment linking guided by NMR experiments. Target-guided approaches, exploiting the biological target to assemble its own inhibitors through dynamic combinatorial chemistry (DCC) and kinetic target-guided synthesis (KTGS), are identified as alternative efficient methods for fragment linking.