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Identification of Structure–Activity Relationships from Screening a Structurally Compact DNA‐Encoded Chemical Library |
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| Authors: | Dr Raphael M Franzini Dr Torun Ekblad Dr Nan Zhong Moreno Wichert Willy Decurtins Angela Nauer Mauro Zimmermann Dr Florent Samain Dr Jörg Scheuermann Dr Peter J Brown Prof?Dr Jonathan Hall Dr Susanne Gräslund Prof?Dr Herwig Schüler Prof?Dr Dario Neri |
| Institution: | 1. Institute of Pharmaceutical Sciences, ETH Zürich, 8093 Zürich (Switzerland);2. Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm (Sweden);3. Structural Genomics Consortium (SGC), University of Toronto, Toronto, M5G 1L7 (Canada);4. Philochem AG, 8112 Otelfingen (Switzerland) |
| Abstract: | 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. |
| Keywords: | combinatorial chemistry drug discovery encoded libraries high‐throughput screening structure– activity relationships |