High-throughput sequencing for the identification of binding molecules from DNA-encoded chemical libraries |
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Authors: | Fabian Buller Martina Steiner Jörg Scheuermann Luca Mannocci Ina Nissen Manuel Kohler Christian Beisel Dario Neri |
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Institution: | 1. Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Wolfgang-Pauli-Strasse 10, CH-8093 Zurich, Switzerland;2. Philochem AG, c/o ETH Zurich, Wolfgang-Pauli-Strasse 10, CH-8093 Zurich, Switzerland;3. Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, CH-4058 Basel, Switzerland;4. Center for Information Sciences/Databases, ETH Zurich, Mattenstrasse 26, CH-4058 Basel, Switzerland |
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Abstract: | DNA-encoded chemical libraries are large collections of small organic molecules, individually coupled to DNA fragments that serve as amplifiable identification bar codes. The isolation of specific binders requires a quantitative analysis of the distribution of DNA fragments in the library before and after capture on an immobilized target protein of interest. Here, we show how Illumina sequencing can be applied to the analysis of DNA-encoded chemical libraries, yielding over 10 million DNA sequence tags per flow-lane. The technology can be used in a multiplex format, allowing the encoding and subsequent sequencing of multiple selections in the same experiment. The sequence distributions in DNA-encoded chemical library selections were found to be similar to the ones obtained using 454 technology, thus reinforcing the concept that DNA sequencing is an appropriate avenue for the decoding of library selections. The large number of sequences obtained with the Illumina method now enables the study of very large DNA-encoded chemical libraries (>500,000 compounds) and reduces decoding costs. |
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