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Journal articles on the topic 'DNA-Encoded Chemical Library'

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Published: 30 June 2021
Last updated: 28 January 2023

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1

Dawadi, Surendra, Nicholas Simmons, Gabriella Miklossy, Kurt M. Bohren, John C. Faver, Melek Nihan Ucisik, Pranavanand Nyshadham, Zhifeng Yu, and Martin M. Matzuk. "Discovery of potent thrombin inhibitors from a protease-focused DNA-encoded chemical library." Proceedings of the National Academy of Sciences 117, no. 29 (July 8, 2020): 16782–89. http://dx.doi.org/10.1073/pnas.2005447117.

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DNA-encoded chemical libraries are collections of compounds individually coupled to unique DNA tags serving as amplifiable identification barcodes. By bridging split-and-pool combinatorial synthesis with the ligation of unique encoding DNA oligomers, million- to billion-member libraries can be synthesized for use in hundreds of healthcare target screens. Although structural diversity and desirable molecular property ranges generally guide DNA-encoded chemical library design, recent reports have highlighted the utility of focused DNA-encoded chemical libraries that are structurally biased for a class of protein targets. Herein, a protease-focused DNA-encoded chemical library was designed that utilizes chemotypes known to engage conserved catalytic protease residues. The three-cycle library features functional moieties such as guanidine, which interacts strongly with aspartate of the protease catalytic triad, as well as mild electrophiles such as sulfonamide, urea, and carbamate. We developed a DNA-compatible method for guanidinylation of amines and reduction of nitriles. Employing these optimized reactions, we constructed a 9.8-million-membered DNA-encoded chemical library. Affinity selection of the library with thrombin, a common protease, revealed a number of enriched features which ultimately led to the discovery of a 1 nM inhibitor of thrombin. Thus, structurally focused DNA-encoded chemical libraries have tremendous potential to find clinically useful high-affinity hits for the rapid discovery of drugs for targets (e.g., proteases) with essential functions in infectious diseases (e.g., severe acute respiratory syndrome coronavirus 2) and relevant healthcare conditions (e.g., male contraception).
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2

Reddavide, Francesco V., Meiying Cui, Weilin Lin, Naiqiang Fu, Stephan Heiden, Helena Andrade, Michael Thompson, and Yixin Zhang. "Second generation DNA-encoded dynamic combinatorial chemical libraries." Chemical Communications 55, no. 26 (2019): 3753–56. http://dx.doi.org/10.1039/c9cc01429b.

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3

Onda, Yuichi, Gabriele Bassi, Abdullah Elsayed, Franziska Ulrich, Sebastian Oehler, Louise Plais, Jörg Scheuermann, and Dario Neri. "A DNA‐Encoded Chemical Library Based on Peptide Macrocycles." Chemistry – A European Journal 27, no. 24 (March 18, 2021): 7160–67. http://dx.doi.org/10.1002/chem.202005423.

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4

Dumelin, Christoph E., Jörg Scheuermann, Samu Melkko, and Dario Neri. "Selection of Streptavidin Binders from a DNA-Encoded Chemical Library." Bioconjugate Chemistry 17, no. 2 (March 2006): 366–70. http://dx.doi.org/10.1021/bc050282y.

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5

Faver, John C., Kevin Riehle, David R. Lancia, Jared B. J. Milbank, Christopher S. Kollmann, Nicholas Simmons, Zhifeng Yu, and Martin M. Matzuk. "Quantitative Comparison of Enrichment from DNA-Encoded Chemical Library Selections." ACS Combinatorial Science 21, no. 2 (January 23, 2019): 75–82. http://dx.doi.org/10.1021/acscombsci.8b00116.

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6

Dumelin, Christoph E, Sabrina Trüssel, Fabian Buller, Eveline Trachsel, Frank Bootz, Yixin Zhang, Luca Mannocci, et al. "A Portable Albumin Binder from a DNA-Encoded Chemical Library." Angewandte Chemie 120, no. 17 (April 14, 2008): 3240–45. http://dx.doi.org/10.1002/ange.200704936.

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7

Stress, Cedric J., Basilius Sauter, Lukas A. Schneider, Timothy Sharpe, and Dennis Gillingham. "A DNA‐Encoded Chemical Library Incorporating Elements of Natural Macrocycles." Angewandte Chemie International Edition 58, no. 28 (July 8, 2019): 9570–74. http://dx.doi.org/10.1002/anie.201902513.

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8

Edwards, Paul. "Design and synthesis of a novel DNA-encoded chemical library." Drug Discovery Today 15, no. 15-16 (August 2010): 690–91. http://dx.doi.org/10.1016/j.drudis.2010.06.013.

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9

Dumelin, Christoph E, Sabrina Trüssel, Fabian Buller, Eveline Trachsel, Frank Bootz, Yixin Zhang, Luca Mannocci, et al. "A Portable Albumin Binder from a DNA-Encoded Chemical Library." Angewandte Chemie International Edition 47, no. 17 (April 14, 2008): 3196–201. http://dx.doi.org/10.1002/anie.200704936.

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10

Shi, Ying, Yan-ran Wu, Jian-qiang Yu, Wan-nian Zhang, and Chun-lin Zhuang. "DNA-encoded libraries (DELs): a review of on-DNA chemistries and their output." RSC Advances 11, no. 4 (2021): 2359–76. http://dx.doi.org/10.1039/d0ra09889b.

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We summarize a series of novel DNA-compatible chemistry reactions for DNA-encoded chemical library (DEL) building blocks and analyse the druggability of screened hit molecules via DELs in the past five years.
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11

Guasch, Laura, Michael Reutlinger, Daniel Stoffler, and Moreno Wichert. "Augmenting Chemical Space with DNA-encoded Library Technology and Machine Learning." CHIMIA International Journal for Chemistry 75, no. 1 (February 28, 2021): 105–7. http://dx.doi.org/10.2533/chimia.2021.105.

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12

Zhou, Yu, Chen Li, Jianzhao Peng, Liangxu Xie, Ling Meng, Qingrong Li, Jianfu Zhang, et al. "DNA-Encoded Dynamic Chemical Library and Its Applications in Ligand Discovery." Journal of the American Chemical Society 140, no. 46 (November 2018): 15859–67. http://dx.doi.org/10.1021/jacs.8b09277.

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13

Ji, Yue, Dongliang Dai, Huadong Luo, Simin Shen, Jing Fan, Zhao Wang, Min Chen, et al. "C–S Coupling of DNA-Conjugated Aryl Iodides for DNA-Encoded Chemical Library Synthesis." Bioconjugate Chemistry 32, no. 4 (March 15, 2021): 685–89. http://dx.doi.org/10.1021/acs.bioconjchem.1c00076.

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14

Kunig, Verena, Marco Potowski, Anne Gohla, and Andreas Brunschweiger. "DNA-encoded libraries – an efficient small molecule discovery technology for the biomedical sciences." Biological Chemistry 399, no. 7 (June 27, 2018): 691–710. http://dx.doi.org/10.1515/hsz-2018-0119.

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Abstract DNA-encoded compound libraries are a highly attractive technology for the discovery of small molecule protein ligands. These compound collections consist of small molecules covalently connected to individual DNA sequences carrying readable information about the compound structure. DNA-tagging allows for efficient synthesis, handling and interrogation of vast numbers of chemically synthesized, drug-like compounds. They are screened on proteins by an efficient, generic assay based on Darwinian principles of selection. To date, selection of DNA-encoded libraries allowed for the identification of numerous bioactive compounds. Some of these compounds uncovered hitherto unknown allosteric binding sites on target proteins; several compounds proved their value as chemical biology probes unraveling complex biology; and the first examples of clinical candidates that trace their ancestry to a DNA-encoded library were reported. Thus, DNA-encoded libraries proved their value for the biomedical sciences as a generic technology for the identification of bioactive drug-like molecules numerous times. However, large scale experiments showed that even the selection of billions of compounds failed to deliver bioactive compounds for the majority of proteins in an unbiased panel of target proteins. This raises the question of compound library design.
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15

Melkko, Samu, Yixin Zhang, Christoph E Dumelin, Jörg Scheuermann, and Dario Neri. "Isolation of High-Affinity Trypsin Inhibitors from a DNA-Encoded Chemical Library." Angewandte Chemie 119, no. 25 (June 18, 2007): 4755–58. http://dx.doi.org/10.1002/ange.200700654.

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16

Melkko, Samu, Yixin Zhang, Christoph E Dumelin, Jörg Scheuermann, and Dario Neri. "Isolation of High-Affinity Trypsin Inhibitors from a DNA-Encoded Chemical Library." Angewandte Chemie International Edition 46, no. 25 (June 18, 2007): 4671–74. http://dx.doi.org/10.1002/anie.200700654.

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17

Gironda-Martínez, Adrián, Dario Neri, Florent Samain, and Etienne J. Donckele. "DNA-Compatible Diazo-Transfer Reaction in Aqueous Media Suitable for DNA-Encoded Chemical Library Synthesis." Organic Letters 21, no. 23 (November 20, 2019): 9555–58. http://dx.doi.org/10.1021/acs.orglett.9b03726.

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18

Zhou, Yu, Jianzhao Peng, Wenyin Shen, and Xiaoyu Li. "Psoralen as an interstrand DNA crosslinker in the selection of DNA-Encoded dynamic chemical library." Biochemical and Biophysical Research Communications 533, no. 2 (December 2020): 215–22. http://dx.doi.org/10.1016/j.bbrc.2020.04.033.

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19

Mannocci, Luca, Yixin Zhang, Jörg Scheuermann, Markus Leimbacher, Gianluca De Bellis, Ermanno Rizzi, Christoph Dumelin, Samu Melkko, and Dario Neri. "High-throughput sequencing allows the identification of binding molecules isolated from DNA-encoded chemical libraries." Proceedings of the National Academy of Sciences 105, no. 46 (November 10, 2008): 17670–75. http://dx.doi.org/10.1073/pnas.0805130105.

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DNA encoding facilitates the construction and screening of large chemical libraries. Here, we describe general strategies for the stepwise coupling of coding DNA fragments to nascent organic molecules throughout individual reaction steps as well as the first implementation of high-throughput sequencing for the identification and relative quantification of the library members. The methodology was exemplified in the construction of a DNA-encoded chemical library containing 4,000 compounds and in the discovery of binders to streptavidin, matrix metalloproteinase 3, and polyclonal human IgG.
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20

Franzini, Raphael M., Angela Nauer, Jörg Scheuermann, and Dario Neri. "Interrogating target-specificity by parallel screening of a DNA-encoded chemical library against closely related proteins." Chemical Communications 51, no. 38 (2015): 8014–16. http://dx.doi.org/10.1039/c5cc01230a.

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21

Ottl, Johannes, Lukas Leder, Jonas V. Schaefer, and Christoph E. Dumelin. "Encoded Library Technologies as Integrated Lead Finding Platforms for Drug Discovery." Molecules 24, no. 8 (April 25, 2019): 1629. http://dx.doi.org/10.3390/molecules24081629.

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The scope of targets investigated in pharmaceutical research is continuously moving into uncharted territory. Consequently, finding suitable chemical matter with current compound collections is proving increasingly difficult. Encoded library technologies enable the rapid exploration of large chemical space for the identification of ligands for such targets. These binders facilitate drug discovery projects both as tools for target validation, structural elucidation and assay development as well as starting points for medicinal chemistry. Novartis internalized two complementing encoded library platforms to accelerate the initiation of its drug discovery programs. For the identification of low-molecular weight ligands, we apply DNA-encoded libraries. In addition, encoded peptide libraries are employed to identify cyclic peptides. This review discusses how we apply these two platforms in our research and why we consider it beneficial to run both pipelines in-house.
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22

Ratnayake, Anokha S., Mark E. Flanagan, Timothy L. Foley, Justin D. Smith, Jillian G. Johnson, Justin Bellenger, Justin I. Montgomery, and Brian M. Paegel. "A Solution Phase Platform to Characterize Chemical Reaction Compatibility with DNA-Encoded Chemical Library Synthesis." ACS Combinatorial Science 21, no. 10 (August 19, 2019): 650–55. http://dx.doi.org/10.1021/acscombsci.9b00113.

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23

Yang, Guanyu, Dou He, Yijun Zhu, Weiwei Zhu, Yang Tan, Xingwen Long, Jinqiao Wan, et al. "Cholesterol-Modified Oligonucleotides as Internal Reaction Controls during DNA-Encoded Chemical Library Synthesis." Bioconjugate Chemistry 32, no. 4 (March 9, 2021): 667–71. http://dx.doi.org/10.1021/acs.bioconjchem.1c00045.

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24

Li, Jian-Yuan, Gabriella Miklossy, Ram K. Modukuri, Kurt M. Bohren, Zhifeng Yu, Murugesan Palaniappan, John C. Faver, Kevin Riehle, Martin M. Matzuk, and Nicholas Simmons. "Palladium-Catalyzed Hydroxycarbonylation of (Hetero)aryl Halides for DNA-Encoded Chemical Library Synthesis." Bioconjugate Chemistry 30, no. 8 (July 22, 2019): 2209–15. http://dx.doi.org/10.1021/acs.bioconjchem.9b00447.

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25

Mannocci, Luca, Samu Melkko, Fabian Buller, Ilona Molnàr, Jean-Paul Gapian Bianké, Christoph E. Dumelin, Jörg Scheuermann, and Dario Neri. "Isolation of Potent and Specific Trypsin Inhibitors from a DNA-Encoded Chemical Library." Bioconjugate Chemistry 21, no. 10 (October 20, 2010): 1836–41. http://dx.doi.org/10.1021/bc100198x.

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26

Shi, Bingbing, Yu Zhou, Yiran Huang, Jianfu Zhang, and Xiaoyu Li. "Recent advances on the encoding and selection methods of DNA-encoded chemical library." Bioorganic & Medicinal Chemistry Letters 27, no. 3 (February 2017): 361–69. http://dx.doi.org/10.1016/j.bmcl.2016.12.025.

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27

Leimbacher, Markus, Yixin Zhang, Luca Mannocci, Michael Stravs, Tim Geppert, Jörg Scheuermann, Gisbert Schneider, and Dario Neri. "Discovery of Small-Molecule Interleukin-2 Inhibitors from a DNA-Encoded Chemical Library." Chemistry - A European Journal 18, no. 25 (May 15, 2012): 7729–37. http://dx.doi.org/10.1002/chem.201200952.

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28

Parandoosh, Z., S. K. Knowles, X. Y. Xiao, C. Zhao, G. S. David, and M. P. Nova. "Encoded chemical synthesis coupled to screening: "Pot Assay"." Combinatorial Chemistry & High Throughput Screening 1, no. 3 (October 1998): 135–42. http://dx.doi.org/10.2174/138620730103220120141950.

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A variety of screening methodologies is available to identify lead compounds. Screening methods that would permit the direct use of libraries made via the Radiofrequency Encoded Combinatorial chemistry paradigm (each individual small molecule in the library is presented separately on an individual encoded support) have the potential to diminish burdensome steps in this process. Here we report on our studies leading to such a direct method, which we have termed a Pot Assay. Pot Assay is a multiplex assay, which simultaneously measures specific binding of a number of ligands to at least one target. Pot Assay uses specific radiofrequency signals to decode compounds that are high affinity binders. We validated this approach by evaluating the interaction of biotin and its analogs with labeled streptavidin. This report introduces Pot Assay as a rapid, simple, sensitive and accurate format for identifying active members of libraries synthesized on solid supports. The success of this study demonstrates the power of coupling Radiofrequency Encoded Combinatorial chemistry and screening. This assay format may be applied to a wide range of screens that are based on binding events: ligand/receptor, inhibitor/enzyme, antigen/antibody, protein/protein, DNA/protein, and RNA/DNA.
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29

Chen, Ying-Chu, John C. Faver, Angela F. Ku, Gabriella Miklossy, Kevin Riehle, Kurt M. Bohren, Melek N. Ucisik, Martin M. Matzuk, Zhifeng Yu, and Nicholas Simmons. "C–N Coupling of DNA-Conjugated (Hetero)aryl Bromides and Chlorides for DNA-Encoded Chemical Library Synthesis." Bioconjugate Chemistry 31, no. 3 (February 5, 2020): 770–80. http://dx.doi.org/10.1021/acs.bioconjchem.9b00863.

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30

Buller, Fabian, Luca Mannocci, Yixin Zhang, Christoph E. Dumelin, Jörg Scheuermann, and Dario Neri. "Design and synthesis of a novel DNA-encoded chemical library using Diels-Alder cycloadditions." Bioorganic & Medicinal Chemistry Letters 18, no. 22 (November 2008): 5926–31. http://dx.doi.org/10.1016/j.bmcl.2008.07.038.

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31

Lemke, Mike, Hannah Ravenscroft, Nicole J. Rueb, Dmitri Kireev, Dana Ferraris, and Raphael M. Franzini. "Integrating DNA-encoded chemical libraries with virtual combinatorial library screening: Optimizing a PARP10 inhibitor." Bioorganic & Medicinal Chemistry Letters 30, no. 19 (October 2020): 127464. http://dx.doi.org/10.1016/j.bmcl.2020.127464.

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32

Franzini, Raphael M., Torun Ekblad, Nan Zhong, Moreno Wichert, Willy Decurtins, Angela Nauer, Mauro Zimmermann, et al. "Identification of Structure-Activity Relationships from Screening a Structurally Compact DNA-Encoded Chemical Library." Angewandte Chemie 127, no. 13 (February 3, 2015): 3999–4003. http://dx.doi.org/10.1002/ange.201410736.

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33

Franzini, Raphael M., Torun Ekblad, Nan Zhong, Moreno Wichert, Willy Decurtins, Angela Nauer, Mauro Zimmermann, et al. "Identification of Structure-Activity Relationships from Screening a Structurally Compact DNA-Encoded Chemical Library." Angewandte Chemie International Edition 54, no. 13 (February 3, 2015): 3927–31. http://dx.doi.org/10.1002/anie.201410736.

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34

Disch, Jeremy S., Jennifer M. Duffy, Esther C. Y. Lee, Diana Gikunju, Betty Chan, Benjamin Levin, Michael I. Monteiro, et al. "Bispecific Estrogen Receptor α Degraders Incorporating Novel Binders Identified Using DNA-Encoded Chemical Library Screening." Journal of Medicinal Chemistry 64, no. 8 (April 12, 2021): 5049–66. http://dx.doi.org/10.1021/acs.jmedchem.1c00127.

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35

Yuen, Lik Hang, Srikanta Dana, Yu Liu, Samuel I. Bloom, Ann-Gerd Thorsell, Dario Neri, Anthony J. Donato, Dmitri Kireev, Herwig Schüler, and Raphael M. Franzini. "A Focused DNA-Encoded Chemical Library for the Discovery of Inhibitors of NAD+-Dependent Enzymes." Journal of the American Chemical Society 141, no. 13 (March 11, 2019): 5169–81. http://dx.doi.org/10.1021/jacs.8b08039.

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36

Samain, Florent, Torun Ekblad, Gediminas Mikutis, Nan Zhong, Mauro Zimmermann, Angela Nauer, Davor Bajic, et al. "Tankyrase 1 Inhibitors with Drug-like Properties Identified by Screening a DNA-Encoded Chemical Library." Journal of Medicinal Chemistry 58, no. 12 (June 10, 2015): 5143–49. http://dx.doi.org/10.1021/acs.jmedchem.5b00432.

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37

Hall, Justin, Timothy L. Foley, Qiuxia Chen, David I. Israel, Yanshan Xu, Kristin K. Ford, Ping Xie, Jing Fan, and Jinqiao Wan. "A simple method for determining compound affinity and chemical yield from DNA-encoded library selections." Biochemical and Biophysical Research Communications 527, no. 1 (June 2020): 250–56. http://dx.doi.org/10.1016/j.bbrc.2020.04.024.

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38

Buller, Fabian, Yixin Zhang, Jörg Scheuermann, Juliane Schäfer, Peter Bühlmann, and Dario Neri. "Discovery of TNF Inhibitors from a DNA-Encoded Chemical Library based on Diels-Alder Cycloaddition." Chemistry & Biology 16, no. 10 (October 2009): 1075–86. http://dx.doi.org/10.1016/j.chembiol.2009.09.011.

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39

Zhu, Zhengrong, LaShadric C. Grady, Yun Ding, Kenneth E. Lind, Christopher P. Davie, Christopher B. Phelps, and Ghotas Evindar. "Development of a Selection Method for Discovering Irreversible (Covalent) Binders from a DNA-Encoded Library." SLAS DISCOVERY: Advancing the Science of Drug Discovery 24, no. 2 (November 1, 2018): 169–74. http://dx.doi.org/10.1177/2472555218808454.

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DNA-encoded libraries (DELs) have been broadly applied to identify chemical probes for target validation and lead discovery. To date, the main application of the DEL platform has been the identification of reversible ligands using multiple rounds of affinity selection. Irreversible (covalent) inhibition offers a unique mechanism of action for drug discovery research. In this study, we report a developing method of identifying irreversible (covalent) ligands from DELs. The new method was validated by using 3C protease (3CP) and on-DNA irreversible tool compounds (rupintrivir derivatives) spiked into a library at the same concentration as individual members of that library. After affinity selections against 3CP, the irreversible tool compounds were specifically enriched compared with the library members. In addition, we compared two immobilization methods and concluded that microscale columns packed with the appropriate affinity resin gave higher tool compound recovery than magnetic beads.
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40

Kuai, Letian, Thomas O’Keeffe, and Christopher Arico-Muendel. "Randomness in DNA Encoded Library Selection Data Can Be Modeled for More Reliable Enrichment Calculation." SLAS DISCOVERY: Advancing the Science of Drug Discovery 23, no. 5 (February 13, 2018): 405–16. http://dx.doi.org/10.1177/2472555218757718.

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DNA Encoded Libraries (DELs) use unique DNA sequences to tag each chemical warhead within a library mixture to enable deconvolution following affinity selection against a target protein. With next-generation sequencing, millions to billions of sequences can be read and counted to report binding events. This unprecedented capability has enabled researchers to synthesize and analyze numerically large chemical libraries. Despite the common perception that each library member undergoes a miniaturized affinity assay, selections with higher complexity libraries often produce results that are difficult to rank order. In this study, we aimed to understand the robustness of DEL selection by examining the sequencing readouts of warheads and chemotype families among a large number of experimentally repeated selections. The results revealed that (1) the output of DEL selection is intrinsically noisy but can be reliably modeled by the Poisson distribution, and (2) Poisson noise is the dominating noise at low copy counts and can be estimated even from a single experiment. We also discuss the shortcomings of data analyses based on directly using copy counts and their linear transformations, and propose a framework that incorporates proper normalization and confidence interval calculation to help researchers better understand DEL data.
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41

Amigo, Jorge, Ramón Rama-Garda, Xabier Bello, Beatriz Sobrino, Jesús de Blas, María Martín-Ortega, Theodore C. Jessop, Ángel Carracedo, María Isabel García Loza, and Eduardo Domínguez. "tagFinder: A Novel Tag Analysis Methodology That Enables Detection of Molecules from DNA-Encoded Chemical Libraries." SLAS DISCOVERY: Advancing the Science of Drug Discovery 23, no. 5 (January 23, 2018): 397–404. http://dx.doi.org/10.1177/2472555217753840.

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Available tools to analyze sequencing data coming from DNA-encoded chemical libraries (DELs) are often limited to in-house methods, which usually rely on strictly looking for the particular DEL structure used. Current methods do not take into account technological errors, such as library codification and sequencing errors, when detecting the sequences. The vast amount of data produced by next-generation sequencing of DEL screens is usually enough to extract the minimum information needed for compound identification. Here, we report a methodology to deconvolute encoding oligonucleotides, thus optimizing the sequencing power regardless of the library size, design complexity, or sequencing technology chosen. tagFinder is a highly flexible tool for fast tag detection and thorough DEL results characterization, which requires minimal hardware resources, scales linearly, and does not introduce any analytical error. The methodology can even deal with sequencing errors and PCR duplicates on single- or double-stranded DNA, enhancing the analytical detection and quantification of molecules and the informativeness of the entire process. Source code is available at https://github.com/jamigo/tagFinder .
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42

Ruff, Yves, Roberto Martinez, Xavier Pellé, Pierre Nimsgern, Pascale Fille, Maxim Ratnikov, and Frédéric Berst. "An Amphiphilic Polymer-Supported Strategy Enables Chemical Transformations under Anhydrous Conditions for DNA-Encoded Library Synthesis." ACS Combinatorial Science 22, no. 3 (February 10, 2020): 120–28. http://dx.doi.org/10.1021/acscombsci.9b00164.

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43

Li, Yizhou, Gunther Zimmermann, Jörg Scheuermann, and Dario Neri. "Quantitative PCR is a Valuable Tool to Monitor the Performance of DNA-Encoded Chemical Library Selections." ChemBioChem 18, no. 9 (March 16, 2017): 848–52. http://dx.doi.org/10.1002/cbic.201600626.

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44

Kim, Dongwook, Yixing Sun, Dan Xie, Kyle E. Denton, Hao Chen, Hang Lin, Michael K. Wendt, Carol Beth Post, and Casey J. Krusemark. "Application of a Substrate-Mediated Selection with c-Src Tyrosine Kinase to a DNA-Encoded Chemical Library." Molecules 24, no. 15 (July 30, 2019): 2764. http://dx.doi.org/10.3390/molecules24152764.

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As aberrant activity of protein kinases is observed in many disease states, these enzymes are common targets for therapeutics and detection of activity levels. The development of non-natural protein kinase substrates offers an approach to protein substrate competitive inhibitors, a class of kinase inhibitors with promise for improved specificity. Also, kinase activity detection approaches would benefit from substrates with improved activity and specificity. Here, we apply a substrate-mediated selection to a peptidomimetic DNA-encoded chemical library for enrichment of molecules that can be phosphorylated by the protein tyrosine kinase, c-Src. Several substrates were identified and characterized for activity. A lead compound (SrcDEL10) showed both the ability to serve as a substrate and to promote ATP hydrolysis by the kinase. In inhibition assays, compounds displayed IC50′s ranging from of 8–100 µM. NMR analysis of SrcDEL10 bound to the c-Src:ATP complex was conducted to characterize the binding mode. An ester derivative of the lead compound demonstrated cellular activity with inhibition of Src-dependent signaling in cell culture. Together, the results show the potential for substrate-mediated selections of DNA-encoded libraries to discover molecules with functions other than simple protein binding and offer a new discovery method for development of synthetic tyrosine kinase substrates.
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45

Rectenwald, Justin M., Shiva Krishna Reddy Guduru, Zhao Dang, Leonard B. Collins, Yi-En Liao, Jacqueline L. Norris-Drouin, Stephanie H. Cholensky, et al. "Design and Construction of a Focused DNA-Encoded Library for Multivalent Chromatin Reader Proteins." Molecules 25, no. 4 (February 22, 2020): 979. http://dx.doi.org/10.3390/molecules25040979.

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Chromatin structure and function, and consequently cellular phenotype, is regulated in part by a network of chromatin-modifying enzymes that place post-translational modifications (PTMs) on histone tails. These marks serve as recruitment sites for other chromatin regulatory complexes that ‘read’ these PTMs. High-quality chemical probes that can block reader functions of proteins involved in chromatin regulation are important tools to improve our understanding of pathways involved in chromatin dynamics. Insight into the intricate system of chromatin PTMs and their context within the epigenome is also therapeutically important as misregulation of this complex system is implicated in numerous human diseases. Using computational methods, along with structure-based knowledge, we have designed and constructed a focused DNA-Encoded Library (DEL) containing approximately 60,000 compounds targeting bi-valent methyl-lysine (Kme) reader domains. Additionally, we have constructed DNA-barcoded control compounds to allow optimization of selection conditions using a model Kme reader domain. We anticipate that this target-class focused approach will serve as a new method for rapid discovery of inhibitors for multivalent chromatin reader domains.
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46

Brown, Dean G., Giles A. Brown, Paolo Centrella, Kaan Certel, Robert M. Cooke, John W. Cuozzo, Niek Dekker, et al. "Agonists and Antagonists of Protease-Activated Receptor 2 Discovered within a DNA-Encoded Chemical Library Using Mutational Stabilization of the Target." SLAS DISCOVERY: Advancing the Science of Drug Discovery 23, no. 5 (January 9, 2018): 429–36. http://dx.doi.org/10.1177/2472555217749847.

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The discovery of ligands via affinity-mediated selection of DNA-encoded chemical libraries is driven by the quality and concentration of the protein target. G-protein-coupled receptors (GPCRs) and other membrane-bound targets can be difficult to isolate in their functional state and at high concentrations, and therefore have been challenging for affinity-mediated selection. Here, we report a successful selection campaign against protease-activated receptor 2 (PAR2). Using a thermo-stabilized mutant of PAR2, we conducted affinity selection using our >100-billion-compound DNA-encoded library. We observed a number of putative ligands enriched upon selection, and subsequent cellular profiling revealed these ligands to comprise both agonists and antagonists. The agonist series shared structural similarity with known agonists. The antagonists were shown to bind in a novel allosteric binding site on the PAR2 protein. This report serves to demonstrate that cell-free affinity selection against GPCRs can be achieved with mutant stabilized protein targets.
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47

Lee, Esther C. Y., Andrew J. McRiner, Katy E. Georgiadis, Julie Liu, Zooey Wang, Andrew D. Ferguson, Benjamin Levin, et al. "Discovery of Novel, Potent Inhibitors of Hydroxy Acid Oxidase 1 (HAO1) Using DNA-Encoded Chemical Library Screening." Journal of Medicinal Chemistry 64, no. 10 (May 6, 2021): 6730–44. http://dx.doi.org/10.1021/acs.jmedchem.0c02271.

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48

Yuen, Lik Hang, Srikanta Dana, Yu Liu, Samuel I. Bloom, Ann-Gerd Thorsell, Dario Neri, Anthony J. Donato, Dmitri Kireev, Herwig Schüler, and Raphael M. Franzini. "Correction to “A Focused DNA-Encoded Chemical Library for the Discovery of Inhibitors of NAD+-Dependent Enzymes”." Journal of the American Chemical Society 143, no. 29 (July 16, 2021): 11272–73. http://dx.doi.org/10.1021/jacs.1c06352.

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49

Sannino, Alessandro, Adrián Gironda-Martínez, Émile M. D. Gorre, Luca Prati, Jacopo Piazzi, Jörg Scheuermann, Dario Neri, Etienne J. Donckele, and Florent Samain. "Critical Evaluation of Photo-cross-linking Parameters for the Implementation of Efficient DNA-Encoded Chemical Library Selections." ACS Combinatorial Science 22, no. 4 (February 28, 2020): 204–12. http://dx.doi.org/10.1021/acscombsci.0c00023.

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50

Shi, Bingbing, Yuqing Deng, Peng Zhao, and Xiaoyu Li. "Selecting a DNA-Encoded Chemical Library against Non-immobilized Proteins Using a “Ligate–Cross-Link–Purify” Strategy." Bioconjugate Chemistry 28, no. 9 (August 10, 2017): 2293–301. http://dx.doi.org/10.1021/acs.bioconjchem.7b00343.

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