A fragment-based approach to probing adenosine recognition sites by using dynamic combinatorial chemistry

D.E. Scott, G.J. Dawes, M. Ando, C. Abell (Lead / Corresponding author), Alessio Ciulli (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    38 Citations (Scopus)

    Abstract

    A new strategy that combines the concepts of fragment-based drug design and dynamic combinatorial chemistry (DCC) for targeting adenosine recognition sites on enzymes is reported. We demonstrate the use of 5'-deoxy-5'- thioadenosine as a noncovalent anchor fragment in dynamic combinatorial libraries templated by Mycobacterium tuberculosis pantothenate synthetase. A benzyl disulfide derivative was identified upon library analysis by HPLC. Structural and binding studies of protein-ligand complexes by X-ray crystallography and isothermal titration calorimetry informed the subsequent optimisation of the DCC hit into a disulfide containing the novel meta-nitrobenzyl fragment that targets the pantoate binding site of pantothenate synthetase. Given the prevalence of adenosine-recognition motifs in enzymes, our results provide a proof-of-concept for using this strategy to probe adjacent pockets for a range of adenosine binding enzymes, including other related adenylate-forming ligases, kinases, and ATPases, as well as NAD(P)(H), CoA and FAD(H) binding proteins.
    Original languageEnglish
    Pages (from-to)2772-2779
    Number of pages8
    JournalChemBioChem
    Volume10
    Issue number17
    DOIs
    Publication statusPublished - 23 Nov 2009

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