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Issue 1, 2015
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DNA display of fragment pairs as a tool for the discovery of novel biologically active small molecules

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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.

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

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Supplementary files

Article information


Submitted
04 Jun 2014
Accepted
16 Sep 2014
First published
22 Sep 2014

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2015,6, 739-744
Article type
Edge Article
Author version available

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

J.-P. Daguer, C. Zambaldo, M. Ciobanu, P. Morieux, S. Barluenga and N. Winssinger, Chem. Sci., 2015, 6, 739
DOI: 10.1039/C4SC01654H

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