Discovery of small-molecule interleukin-2 inhibitors from a DNA-encoded chemical library |
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Authors: | Leimbacher Markus Zhang Yixin Mannocci Luca Stravs Michael Geppert Tim Scheuermann Jörg Schneider Gisbert Neri Dario |
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Institution: | Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Wolfgang Pauli-Str. 10, 8093 Zürich, Switzerland. |
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Abstract: | Libraries of chemical compounds individually coupled to encoding DNA tags (DNA-encoded chemical libraries) hold promise to facilitate exceptionally efficient ligand discovery. We constructed a high-quality DNA-encoded chemical library comprising 30,000 drug-like compounds; this was screened in 170 different affinity capture experiments. High-throughput sequencing allowed the evaluation of 120?million DNA codes for a systematic analysis of selection strategies and statistically robust identification of binding molecules. Selections performed against the tumor-associated antigen carbonic anhydrase?IX (CA?IX) and the pro-inflammatory cytokine interleukin-2 (IL-2) yielded potent inhibitors with exquisite target specificity. The binding mode of the revealed pharmacophore against IL-2 was confirmed by molecular docking. Our findings suggest that DNA-encoded chemical libraries allow the facile identification of drug-like ligands principally to any protein of choice, including molecules capable of disrupting high-affinity protein-protein interactions. |
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