From Small to Powerful: The Fragments Universe and its “Chem-Appeal”
While increasing expertise in molecular biology and proteomics is markedly speeding up the target elucidation
process, various strategies have been proposed that improve the chances of identifying active molecules. Among them, the
Fragment Based Drug Design (FBDD) is surely worth noting. The FBDD entails the screening of a small number of low
molecular weight compounds in the hopes of finding even low affine but high ligand efficient fragments that have high
probability to became drug candidates. Since 1996, when the first paper on FBDD was reported, the potentialities of this
strategy became progressively more apparent as testified by the growing number of publications. Many drug discovery
projects started with the identification of fragments which after the optimization gave many molecules close to the approval
and one marketed drug Vemurafenib, approved in 2011.
A preamble that highlights the advantages of dealing with simple and “very small” molecules over conventional drug-like
compounds will be herein given prior to discussing the canonical FBDD stages, from fragment library design, to the different
screening methods concluding with the various optimization strategies, in an attempt to illustrate the whole FBDD
workflow while discussing the most recent and successful applications.
While this review is a tribute to the success achieved by the researchers in this field, it is particularly addressed to scientists
who want to become aware of the versatility and potentiality of FBDD.
Keywords: FBDD, fragment library design, fragment optimization, NMR screening, SPR-based screening, X-ray crystallography.
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