DNA display of fragment pairs as a tool for the discovery of novel biologically active small molecules

Chemical Science
J-P DaguerNicolas Winssinger

Abstract

Fragment-based lead discovery has proven to be a powerful method in the drug discovery process. The combinatorial output that is accessible by combining fragments is very attractive; however, identifying fragment pairs that bind synergistically and linking them productively can be challenging. Several technologies have now been established to prepare and screen nucleic acid-encoded libraries (ssDNA, dsDNA, PNA), and it has been shown that pairs of molecules combined by hybridization can bind synergistically to a target. Herein we apply this concept to combinatorially pair two libraries of small molecule fragments, use the fittest fragments supplemented with closely related analogs to build a focused library covalently linking the fragments with different spacers, and apply this strategy to the discovery of a potent ligand for Hsp70.

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Citations

Jun 27, 2015·Beilstein Journal of Organic Chemistry·Alexandre Novoa, Nicolas Winssinger
Apr 14, 2020·Angewandte Chemie·Hongtao XuRichard A Lerner
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Methods Mentioned

BETA
affinity purification
chip
pull-down
affinity measurements
pull down

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