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

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.

SUBMITTER: Daguer JP

PROVIDER: S-EPMC6085657 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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

Daguer J-P JP Zambaldo C C Ciobanu M M Morieux P P Barluenga S S Winssinger N N

Chemical science 20140922 1

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 syn ...[more]

PMID: 30154995

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