Design, synthesis and selection of DNA-encoded small-molecule libraries

• Published in: Nature Chemical Biology Vol. 5; no. 9; pp. 647 - 654
• Main Authors: Morgan, Barry A, Clark, Matthew A, Acharya, Raksha A, Arico-Muendel, Christopher C, Belyanskaya, Svetlana L, Benjamin, Dennis R, Carlson, Neil R, Centrella, Paolo A, Chiu, Cynthia H, Creaser, Steffen P, Cuozzo, John W, Davie, Christopher P, Ding, Yun, Franklin, G Joseph, Franzen, Kurt D, Gefter, Malcolm L, Hale, Steven P, Hansen, Nils J V, Israel, David I, Jiang, Jinwei, Kavarana, Malcolm J, Kelley, Michael S, Kollmann, Christopher S, Li, Fan, Lind, Kenneth, Mataruse, Sibongile, Medeiros, Patricia F, Messer, Jeffrey A, Myers, Paul, O'Keefe, Heather, Oliff, Matthew C, Rise, Cecil E, Satz, Alexander L, Skinner, Steven R, Svendsen, Jennifer L, Tang, Lujia, van Vloten, Kurt, Wagner, Richard W, Yao, Gang, Zhao, Baoguang
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2009; Nature Publishing Group
• Subjects: Animals; Aurora Kinases; Biochemical Engineering; Biochemistry; Biomedical research; Bioorganic Chemistry; Cell Biology; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Combinatorial Chemistry Techniques; Deoxyribonucleic acid; DNA; DNA - chemistry; DNA - genetics; Drug Design; Models, Molecular; Molecular biology; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Proteins; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology
• ISSN: 1552-4450; 1548-7105; 1552-4469
• DOI: 10.1038/nchembio.211

Biochemical combinatorial techniques such as phage display, RNA display and oligonucleotide aptamers have proven to be reliable methods for generation of ligands to protein targets. Adapting these techniques to small synthetic molecules has been a long-sought goal. We report the synthesis and interrogation of an 800-million-member DNA-encoded library in which small molecules are covalently attached to an encoding oligonucleotide. The library was assembled by a combination of chemical and enzymatic synthesis, and interrogated by affinity selection. We describe methods for the selection and deconvolution of the chemical display library, and the discovery of inhibitors for two enzymes: Aurora A kinase and p38 MAP kinase.