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Identification of Structure–Activity Relationships from Screening a Structurally Compact DNA‐Encoded Chemical Library
Author(s) -
Franzini Raphael M.,
Ekblad Torun,
Zhong Nan,
Wichert Moreno,
Decurtins Willy,
Nauer Angela,
Zimmermann Mauro,
Samain Florent,
Scheuermann Jörg,
Brown Peter J.,
Hall Jonathan,
Gräslund Susanne,
Schüler Herwig,
Neri Dario
Publication year - 2015
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201410736
Subject(s) - dna , computational biology , affinities , binding affinities , chemistry , dna sequencing , drug discovery , combinatorial chemistry , small molecule , identification (biology) , chemical biology , biochemistry , stereochemistry , biology , botany , receptor
Methods for the rapid and inexpensive discovery of hit compounds are essential for pharmaceutical research and DNA‐encoded chemical libraries represent promising tools for this purpose. We here report on the design and synthesis of DAL‐100K, a DNA‐encoded chemical library containing 103 200 structurally compact compounds. Affinity screening experiments and DNA‐sequencing analysis provided ligands with nanomolar affinities to several proteins, including prostate‐specific membrane antigen and tankyrase 1. Correlations of sequence counts with binding affinities and potencies of enzyme inhibition were observed and enabled the identification of structural features critical for activity. These results indicate that libraries of this type represent a useful source of small‐molecule binders for target proteins of pharmaceutical interest and information on structural features important for binding.