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How to get GAT

ChemMedChem, published online 11 June 2012, doi:10.1002/cmdc.201200201

MS has become a useful tool for identifying compounds that bind targets of interest in the late stages of chemical screening efforts. Sindelar and Wanner now introduce MS to earlier stages of the screening process by extending its ability to characterize single compounds in competition studies to libraries of compounds. The authors applied MS binding assays to compound libraries generated from dynamic combinatorial chemistry (DCC). Whereas 'adaptive' libraries are generated by fundamental and efficient chemical reactions in the presence of the protein target, which serves to shift the equilibrium toward the best binders, the authors use these reactions for the generation of pseudostatic libraries. The feasibility of this concept, which distinctly facilitates hit detection as library components are present in almost equal amounts, was demonstrated with the GABA transporter GAT1. The authors used DCC to generate nine small hydrazone-based libraries under conditions promoting maximal product formation and compatibility with a known GAT1 MS binding assay, which was performed in parallel. Each compound from the two most potent libraries in the binding assay was then tested individually to identify one from each library that bound GAT1 with high affinity and inhibited transporter activity. Competitive MS binding assays could prove to be a powerful readout for finding new inhibitors for unique targets.


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Bucci, M. How to get GAT. Nat Chem Biol 8, 678 (2012).

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