A chelator fragment library based on a variety of metal binding groups was screened against a metalloproteinase. Lead hits were identified and an expanded library of select compounds was synthesized, resulting in numerous high-affinity hits against several metalloprotein targets. The findings clearly demonstrate that chelators can be used to generate libraries suitable for fragmentbased lead design (FBLD) directed at important metalloproteins. Keywords chelators; fragment-based lead design;

more »

... aries; metalloproteins; zinc Fragment-based lead design (FBLD), sometimes referred to as fragment-based drug discovery (FBDD), is an increasingly important strategy for the discovery of biologically active compounds. [1] FBLD generally uses libraries consisting of modest collections (100-1000 compounds) of small molecular fragments (MW <300 amu) that are screened against targets of interest. [2] Although such fragments do not bind as tightly (K d values in the micro-to millimolar range) as more complex molecules, including those used in high-throughput screening (HTS) approaches, they can provide 'hits' that serve as efficient starting structures for the development of potent inhibitors. Fragments that bind to a target are identified, after which one of two approaches is generally pursued: a) a single fragment can be elaborated in order to obtain a tight binder; or b) multiple fragments binding at adjacent and distinct sites can be connected by an appropriate linker to obtain a potent inhibitor. Compared to HTS, FBLD is purported to have several advantages, including a more efficient exploration of chemically diverse space and higher ligand efficiencies. Although the application of FBLD to metalloprotein targets of medicinal interest has been described,[3] the design, synthesis, and use of general fragment libraries based on metal Correspondence to: Maurizio