Identification of Structure–Activity Relationships from Screening a Structurally Compact DNA‐Encoded Chemical Library

作者：Raphael M. Franzini, T. Ekblad, Nan Zhong, Moreno Wichert, Willy Decurtins, Angela Nauer, Mauro Zimmermann, Florent Samain, Jörg Scheuermann, Peter J. Brown, Jonathan Hall, S. Gräslund, H. Schüler, Dario Neri · 发表于：Angewandte Chemie International Edition · 年份：2015 · DOI：10.1002/anie.201410736 · 被引用次数：98 · 研究领域：Chemical Synthesis and Analysis、Click Chemistry and Applications、Monoclonal and Polyclonal Antibodies Research

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.