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

Meiying Cui, Dzung Nguyen, Michelle Patino Gaillez, Stephan Heiden, Weilin Lin, Michael Thompson, Francesco V. Reddavide (), Qinchang Chen () and Yixin Zhang ()
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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
Yixin Zhang: Technische Universität Dresden

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37071-1

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