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Trio-pharmacophore DNA-encoded chemical library for simultaneous selection of fragments and linkers

Author

Listed:
  • Meiying Cui

    (Technische Universität Dresden)

  • Dzung Nguyen

    (DyNAbind GmbH)

  • Michelle Patino Gaillez

    (Technische Universität Dresden)

  • Stephan Heiden

    (DyNAbind GmbH)

  • Weilin Lin

    (Technische Universität Dresden)

  • Michael Thompson

    (DyNAbind GmbH)

  • Francesco V. Reddavide

    (DyNAbind GmbH)

  • Qinchang Chen

    (Research Institute of Intelligent Computing, Zhejiang Lab
    Tongji University)

  • Yixin Zhang

    (Technische Universität Dresden)

Abstract

The split-and-pool method has been widely used to synthesize chemical libraries of a large size for early drug discovery, albeit without the possibility of meaningful quality control. In contrast, a self-assembled DNA-encoded chemical library (DEL) allows us to construct an m x n-member library by mixing an m-member and an n-member pre-purified sub-library. Herein, we report a trio-pharmacophore DEL (T-DEL) of m x l x n members through assembling three pre-purified and validated sub-libraries. The middle sub-library is synthesized using DNA-templated synthesis with different reaction mechanisms and designed as a linkage connecting the fragments displayed on the flanking two sub-libraries. Despite assembling three fragments, the resulting compounds do not exceed the up-to-date standard of molecular weight regarding drug-likeness. We demonstrate the utility of T-DEL in linker optimization for known binding fragments against trypsin and carbonic anhydrase II and by de novo selections against matrix metalloprotease-2 and −9.

Suggested Citation

  • Meiying Cui & Dzung Nguyen & Michelle Patino Gaillez & Stephan Heiden & Weilin Lin & Michael Thompson & Francesco V. Reddavide & Qinchang Chen & Yixin Zhang, 2023. "Trio-pharmacophore DNA-encoded chemical library for simultaneous selection of fragments and linkers," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37071-1
    DOI: 10.1038/s41467-023-37071-1
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    References listed on IDEAS

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    1. Nuria Plattner & Frank Noé, 2015. "Protein conformational plasticity and complex ligand-binding kinetics explored by atomistic simulations and Markov models," Nature Communications, Nature, vol. 6(1), pages 1-10, November.
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