Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Primer
  • Published:

DNA-encoded chemical libraries

Abstract

DNA-encoded chemical library (DECL) technology is used by the pharmaceutical industry to discover small molecules capable of modulating biologically relevant targets. DECL synthesis starts with an oligonucleotide that contains a chemical linker moiety, and proceeds through iterative cycles of DNA barcode elongation and chemical synthesis. DECL selections require little protein, minimal assay development and no specialized instrumentation. Parallel DECL selections can be easily conducted, making it possible to directly compare results across different conditions. The acquisition of building blocks is a large impediment when setting up a successful DECL platform. A potential solution is the sharing of building blocks between different labs, or the high-throughput parallel synthesis of novel building blocks. DNA-compatible reactions are required to join the building blocks together, and numerous academic labs have recently taken up this challenge. DECLs exist as unpurified mixtures, complicating data analysis. Machine learning may provide an improved ability to interrogate these data. DECL selections are largely limited to soluble purified proteins. However, progress has been made towards cell surface and in-cell selections. Publication guidelines are needed to better enable reproducibility; for example, the quantification of amplifiable DNA by quantitative PCR, and more complete datasets and building block lists, should be provided.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Synthesis of DNA-encoded chemical libraries.
Fig. 2: Affinity-based DECL selections against an immobilized target protein.
Fig. 3: Analysis of DECL data and hit optimization.
Fig. 4: Examples of DECL applications for hit discovery.
Fig. 5: Reproducibility of DECL selections.

Similar content being viewed by others

References

  1. Leveridge, M., Chung, C.-W., Gross, J. W., Phelps, C. B. & Green, D. Integration of lead discovery tactics and the evolution of the lead discovery toolbox. SLAS Discov. 23, 881–897 (2018).

    Article  Google Scholar 

  2. Brenner, S. & Lerner, R. A. Encoded combinatorial chemistry. Proc. Natl Acad. Sci. USA 89, 5381–5383 (1992).

    Article  ADS  Google Scholar 

  3. Melkko, S., Scheuermann, J., Dumelin, C. E. & Neri, D. Encoded self-assembling chemical libraries. Nat. Biotechnol. 22, 568–574 (2004).

    Article  Google Scholar 

  4. Clark, M. A. et al. Design, synthesis and selection of DNA-encoded small-molecule libraries. Nat. Chem. Biol. 5, 647–654 (2009). First report of the synthesis of a numerically large DNA-encoded library using split-and-pool combinatorial chemistry and double-stranded DNA coding fragments.

    Article  Google Scholar 

  5. Mannocci, L. et al. High-throughput sequencing allows the identification of binding molecules isolated from DNA-encoded chemical libraries. Proc. Natl Acad. Sci. USA 105, 17670–17675 (2008).

    Article  ADS  Google Scholar 

  6. Gartner, Z. J. DNA-templated organic synthesis and selection of a library of macrocycles. Science 305, 1601–1605 (2004).

    Article  ADS  Google Scholar 

  7. Xia, B. et al. DNA-encoded library hit confirmation: bridging the gap between On-DNA and Off-DNA chemistry. ACS Med. Chem. Lett. 12, 1166–1172 (2021).

    Article  Google Scholar 

  8. Franzini, R. et al. DNA-encoded chemical libraries: advancing beyond conventional small-molecule libraries. Acc. Chem. Res. 47, 1247–1255 (2014).

    Article  Google Scholar 

  9. Song, M. & Hwang, G. T. DNA-encoded library screening as core platform technology in drug discovery: its synthetic method development and applications in DEL synthesis. J. Med. Chem. 63, 6578–6599 (2020).

    Article  Google Scholar 

  10. Goodnow, R. A., Dumelin, C. E. & Keefe, A. D. DNA-encoded chemistry: enabling the deeper sampling of chemical space. Nat. Rev. Drug Discov. 16, 131–147 (2017).

    Article  Google Scholar 

  11. Kodadek, T. The rise, fall and reinvention of combinatorial chemistry. Chem. Commun. 47, 9757–9763 (2011).

    Article  Google Scholar 

  12. [No authors listed.] Detection of protein-protein interactions using the GST fusion protein pull-down technique. Nat. Methods 1, 275–276 (2004).

    Article  Google Scholar 

  13. Decurtins, W. et al. Automated screening for small organic ligands using DNA-encoded chemical libraries. Nat. Protoc. 11, 764–780 (2016).

    Article  Google Scholar 

  14. Murray, C. W. & Rees, D. C. The rise of fragment-based drug discovery. Nat. Chem. 1, 187–192 (2009).

    Article  Google Scholar 

  15. Gorgulla, C. et al. An open-source drug discovery platform enables ultra-large virtual screens. Nature 580, 663–668 (2020).

    Article  ADS  Google Scholar 

  16. Furka, A., Sebestyén, F., Asgedom, M. & Dibó, G. General method for rapid synthesis of multicomponent peptide mixtures. Int. J. Pept. Protein Res. 37, 487–493 (1991).

    Article  Google Scholar 

  17. Blakskjaer, P., Heitner, T. & Hansen, N. J. V. Fidelity by design: yoctoreactor and binder trap enrichment for small-molecule DNA-encoded libraries and drug discovery. Curr. Opin. Chem. Biol. 26, 62–71 (2015).

    Article  Google Scholar 

  18. Usanov, D. L., Chan, A. I., Maianti, J. P. & Liu, D. R. Second-generation DNA-templated macrocycle libraries for the discovery of bioactive small molecules. Nat. Chem. 10, 704–714 (2018).

    Article  Google Scholar 

  19. Reddavide, F. V., Lin, W., Lehnert, S. & Zhang, Y. DNA-encoded dynamic combinatorial chemical libraries. Angew. Chem. 127, 8035–8039 (2015).

    Article  ADS  Google Scholar 

  20. O’Reilly, R. K., Turberfield, A. J. & Wilks, T. R. The evolution of DNA-templated synthesis as a tool for materials discovery. Acc. Chem. Res. 50, 2496–2509 (2017).

    Article  Google Scholar 

  21. MacConnell, A. B., McEnaney, P. J., Cavett, V. J. & Paegel, B. M. DNA-encoded solid-phase synthesis: encoding language design and complex oligomer library synthesis. ACS Comb. Sci. 17, 518–534 (2015).

    Article  Google Scholar 

  22. Paciaroni, N. G., Ndungu, J. M. & Kodadek, T. Solid-phase synthesis of DNA-encoded libraries via an “aldehyde explosion” strategy. Chem. Commun. 56, 4656–4659 (2020).

    Article  Google Scholar 

  23. Satz, A. L., Kuai, L. & Peng, X. Selections and screenings of DNA-encoded chemical libraries against enzyme and cellular targets. Bioorg. Med. Chem. Lett. 39, 127851 (2021).

    Article  Google Scholar 

  24. Scheuermann, J. & Neri, D. Dual-pharmacophore DNA-encoded chemical libraries. Curr. Opin. Chem. Biol. 26, 99–103 (2015).

    Article  Google Scholar 

  25. Wichert, M. et al. Dual-display of small molecules enables the discovery of ligand pairs and facilitates affinity maturation. Nat. Chem. 7, 241–249 (2015). Discovery of an in vivo carbonic anhydrase IX binder (for tumour targeting) using a DECL constructed by hybridizing purified small-molecule single-stranded DNA-conjugated precursors.

    Article  Google Scholar 

  26. Kazmierski, W. M. et al. DNA encoded library technology-based discovery, lead optimization and prodrug strategy toward structurally-unique indoleamine 2,3-dioxygenase (IDO1) inhibitors. J. Med. Chem. 63, 3552–3562 (2020).

    Article  Google Scholar 

  27. Ahn, S. et al. Allosteric “beta-blocker” isolated from a DNA-encoded small molecule library. Proc. Natl Acad. Sci. USA 114, 1708–1713 (2017).

    Article  Google Scholar 

  28. Wood, E. R. et al. The role of phosphodiesterase 12 (PDE12) as a negative regulator of the innate immune response and the discovery of antiviral inhibitors. J. Biol. Chem. 290, 19681–19696 (2015).

    Article  Google Scholar 

  29. Yang, H. et al. Discovery of a potent class of PI3Kα inhibitors with unique binding mode via encoded library technology (ELT). ACS Med. Chem. Lett. 6, 531–536 (2015).

    Article  Google Scholar 

  30. Zhu, H., Flanagan, M. E. & Stanton, R. V. Designing DNA encoded libraries of diverse products in a focused property space. J. Chem. Inf. Model. 59, 4645–4653 (2019).

    Article  Google Scholar 

  31. Martín, A., Nicolaou, C. A. & Toledo, M. A. Navigating the DNA encoded libraries chemical space. Commun. Chem. 3, 1–9 (2020).

    Article  Google Scholar 

  32. Götte, K., Chines, S. & Brunschweiger, A. Reaction development for DNA-encoded library technology: from evolution to revolution? Tetrahedron Lett. 61, 151889 (2020).

    Article  Google Scholar 

  33. de Pedro Beato, E. et al. Mild and efficient palladium-mediated C–N cross-coupling reaction between DNA-conjugated aryl bromides and aromatic amines. ACS Comb. Sci. 21, 69–74 (2019).

    Article  Google Scholar 

  34. Satz, A. L. et al. DNA compatible multistep synthesis and applications to DNA encoded libraries. Bioconjug. Chem. 26, 1623–1632 (2015). First disclosure of a large number of DNA-compatible chemistries commonly used to construct DECLs.

    Article  Google Scholar 

  35. Phelan, J. P. et al. Open-air alkylation reactions in photoredox-catalyzed DNA-encoded library synthesis. J. Am. Chem. Soc. 141, 3723–3732 (2019).

    Article  Google Scholar 

  36. Škopic´, M. K. et al. Micellar Brønsted acid mediated synthesis of DNA-tagged heterocycles. J. Am. Chem. Soc. 141, 10546–10555 (2019).

    Article  Google Scholar 

  37. Potowski, M. et al. Screening of metal ions and organocatalysts on solid support-coupled DNA oligonucleotides guides design of DNA-encoded reactions. Chem. Sci. 10, 10481–10492 (2019).

    Article  Google Scholar 

  38. Flood, D. T. et al. Expanding reactivity in DNA-encoded library synthesis via reversible binding of DNA to an inert quaternary ammonium support. J. Am. Chem. Soc. 141, 9998–10006 (2019).

    Article  Google Scholar 

  39. Favalli, N., Bassi, G., Scheuermann, J. & Neri, D. DNA-encoded chemical libraries: achievements and remaining challenges. FEBS Lett. 592, 2168–2180 (2018).

    Article  Google Scholar 

  40. Li, Y., Zimmermann, G., Scheuermann, J. & Neri, D. Quantitative PCR is a valuable tool to monitor the performance of DNA-encoded chemical library selections. Chembiochem Eur. J. Chem. Biol. 18, 848–852 (2017).

    Article  Google Scholar 

  41. Li, Y. et al. Optimized reaction conditions for amide bond formation in DNA-encoded combinatorial libraries. ACS Comb. Sci. 18, 438–443 (2016).

    Article  Google Scholar 

  42. Franzini, R. M. et al. Identification of structure–activity relationships from screening a structurally compact DNA-encoded chemical library. Angew. Chem. Int. Ed. 54, 3927–3931 (2015).

    Article  Google Scholar 

  43. Ruff, Y. & Berst, F. Efficient copper-catalyzed amination of DNA-conjugated aryl iodides under mild aqueous conditions. MedChemComm 9, 1188–1193 (2018).

    Article  Google Scholar 

  44. Deng, H. et al. Discovery, SAR, and X-ray binding mode study of BCATm inhibitors from a novel DNA-encoded library. ACS Med. Chem. Lett. 6, 919–924 (2015).

    Article  Google Scholar 

  45. Gerry, C. J., Wawer, M. J., Clemons, P. A. & Schreiber, S. L. DNA barcoding a complete matrix of stereoisomeric small molecules. J. Am. Chem. Soc. 141, 10225–10235 (2019).

    Article  Google Scholar 

  46. Wang, X. et al. Diversified strategy for the synthesis of DNA-encoded oxindole libraries. Chem. Sci. 12, 2841–2847 (2021).

    Article  Google Scholar 

  47. Faver, J. C. et al. Quantitative comparison of enrichment from DNA-encoded chemical library selections. ACS Comb. Sci. 21, 75–82 (2019).

    Article  Google Scholar 

  48. Litovchick, A. et al. Encoded library synthesis using chemical ligation and the discovery of sEH inhibitors from a 334-million member library. Sci. Rep. 5, 10916 (2015).

    Article  ADS  Google Scholar 

  49. Ratnayake, A. S. et al. A solution phase platform to characterize chemical reaction compatibility with DNA-encoded chemical library synthesis. ACS Comb. Sci. 21, 650–655 (2019).

    Article  Google Scholar 

  50. Kuai, L., O’Keeffe, T. & Arico-Muendel, C. Randomness in DNA encoded library selection data can be modeled for more reliable enrichment calculation. SLAS Discov. 23, 405–416 (2018).

    Article  Google Scholar 

  51. Guilinger, J. P. et al. Novel irreversible covalent BTK inhibitors discovered using DNA-encoded chemistry. Bioorg. Med. Chem. 42, 116223 (2021).

    Article  Google Scholar 

  52. Richter, H. et al. DNA-encoded library-derived DDR1 inhibitor prevents fibrosis and renal function loss in a genetic mouse model of alport syndrome. ACS Chem. Biol. 14, 37–49 (2019). Use of DECL parallel selections to discover a selective, and in vivo active, kinase inhibitor.

    Article  Google Scholar 

  53. McCafferty, J., Griffiths, A. D., Winter, G. & Chiswell, D. J. Phage antibodies: filamentous phage displaying antibody variable domains. Nature 348, 552–554 (1990).

    Article  ADS  Google Scholar 

  54. Block, H. et al. Immobilized-metal affinity chromatography (IMAC). Methods Enzymol. 463, 439–473 (2009).

    Article  Google Scholar 

  55. McCarthy, K. A. et al. The impact of variable selection coverage on detection of ligands from a DNA-encoded library screen. SLAS Discov. 25, 515–522 (2020).

    Article  Google Scholar 

  56. Satz, A. L. Simulated screens of DNA encoded libraries: the potential influence of chemical synthesis fidelity on interpretation of structure–activity relationships. ACS Comb. Sci. 18, 415–424 (2016).

    Article  Google Scholar 

  57. Machutta, C. A. et al. Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening. Nat. Commun. 8, 16081 (2017).

    Article  ADS  Google Scholar 

  58. Bassi, G. et al. A single-stranded DNA-encoded chemical library based on a stereoisomeric scaffold enables ligand discovery by modular assembly of building blocks. Adv. Sci. 7, 2001970 (2020).

    Article  Google Scholar 

  59. Favalli, N. et al. Stereo- and regiodefined DNA-encoded chemical libraries enable efficient tumour-targeting applications. Nat. Chem. 13, 540–548 (2021).

    Article  Google Scholar 

  60. Bassi, G. et al. Comparative evaluation of DNA-encoded chemical selections performed using DNA in single-stranded or double-stranded format. Biochem. Biophys. Res. Commun. 533, 223–229 (2020).

    Article  Google Scholar 

  61. Zhou, Y. et al. DNA-encoded dynamic chemical library and its applications in ligand discovery. J. Am. Chem. Soc. 140, 15859–15867 (2018).

    Article  Google Scholar 

  62. Eidam, O. & Satz, A. L. Analysis of the productivity of DNA encoded libraries. MedChemComm 7, 1323–1331 (2016).

    Article  Google Scholar 

  63. Sannino, A. et al. Quantitative assessment of affinity selection performance by using DNA-encoded chemical libraries. Chembiochem 20, 955–962 (2019).

    Article  Google Scholar 

  64. Foley, T. L. et al. Selecting approaches for hit identification and increasing options by building the efficient discovery of actionable chemical matter from DNA-encoded libraries. SLAS Discov. 26, 263–280 (2021).

    Article  Google Scholar 

  65. Buller, F., Mannocci, L., Scheuermann, J. & Neri, D. Drug discovery with DNA-encoded chemical libraries. Bioconjug. Chem. 21, 1571–1580 (2010).

    Article  Google Scholar 

  66. Wu, Z. et al. Cell-based selection expands the utility of DNA-encoded small-molecule library technology to cell surface drug targets: identification of novel antagonists of the NK3 tachykinin receptor. ACS Comb. Sci. 17, 722–731 (2015). First report of a DECL selection against a target overexpressed on the surface of cells.

    Article  Google Scholar 

  67. Belyanskaya, S. L., Ding, Y., Callahan, J. F., Lazaar, A. L. & Israel, D. I. Discovering drugs with DNA-encoded library technology: from concept to clinic with an inhibitor of soluble epoxide hydrolase. Chembiochem 18, 837–842 (2017).

    Article  Google Scholar 

  68. Harris, P. A. et al. DNA-encoded library screening identifies benzo[b][1,4]oxazepin-4-ones as highly potent and monoselective receptor interacting protein 1 kinase inhibitors. J. Med. Chem. 59, 2163–2178 (2016). Describes the advancement of a DECL hit molecule to the clinic.

    Article  Google Scholar 

  69. Cuozzo, J. W. et al. Novel autotaxin inhibitor for the treatment of idiopathic pulmonary fibrosis: a clinical candidate discovered using DNA-encoded chemistry. J. Med. Chem. 63, 7840–7856 (2020).

    Article  Google Scholar 

  70. Reiher, C. A., Schuman, D. P., Simmons, N. & Wolkenberg, S. E. Trends in hit-to-lead optimization following DNA-encoded library screens. ACS Med. Chem. Lett. 12, 343–350 (2021).

    Article  Google Scholar 

  71. Gilmartin, A. G. et al. Allosteric Wip1 phosphatase inhibition through flap-subdomain interaction. Nat. Chem. Biol. 10, 181–187 (2014). Describes the optimization of a hit molecule discovered by a combination of DECL selection and biochemical high-throughput screening.

    Article  Google Scholar 

  72. Wellaway, C. R. et al. Discovery of a bromodomain and extraterminal inhibitor with a low predicted human dose through synergistic use of encoded library technology and fragment screening. J. Med. Chem. 63, 714–746 (2020). Describes the optimization of a hit molecule discovered by a combination of DECL selection and fragment screening.

    Article  Google Scholar 

  73. Deng, H. et al. Discovery and optimization of potent, selective, and in vivo efficacious 2-Aryl benzimidazole BCATm inhibitors. ACS Med. Chem. Lett. 7, 379–384 (2016).

    Article  Google Scholar 

  74. Harris, P. A. et al. Discovery of a first-in-class receptor interacting protein 1 (RIP1) kinase specific clinical candidate (GSK2982772) for the treatment of inflammatory diseases. J. Med. Chem. 60, 1247–1261 (2017).

    Article  Google Scholar 

  75. Satz, A. L., Kollmann, C. S., Paegel, B. M. in 2020 Medicinal Chemistry Reviews Volume 55 Ch. 23 (ACS, 2020).

  76. Litovchick, A. et al. Novel nucleic acid binding small molecules discovered using DNA-encoded chemistry. Molecules 24, 2026 (2019).

    Article  Google Scholar 

  77. Mukherjee, H. et al. PEARL-seq: a photoaffinity platform for the analysis of small molecule-RNA interactions. ACS Chem. Biol. 15, 2374–2381 (2020).

    Article  Google Scholar 

  78. Cai, B. et al. Selection of DNA-encoded libraries to protein targets within and on living cells. J. Am. Chem. Soc. 141, 17057–17061 (2019).

    Article  Google Scholar 

  79. McGregor, L. M., Gorin, D. J., Dumelin, C. E. & Liu, D. R. Interaction-dependent PCR: identification of ligand−target pairs from libraries of ligands and libraries of targets in a single solution-phase experiment. J. Am. Chem. Soc. 132, 15522–15524 (2010).

    Article  Google Scholar 

  80. Petersen, L. K. et al. Novel p38α MAP kinase inhibitors identified from yoctoReactor DNA-encoded small molecule library. MedChemComm 7, 1332–1339 (2016).

    Article  Google Scholar 

  81. Li, G. et al. Photoaffinity labeling of small-molecule-binding proteins by DNA-templated chemistry. Angew. Chem. Int. Ed. 52, 9544–9549 (2013).

    Article  Google Scholar 

  82. Zhao, P. et al. Selection of DNA-encoded small molecule libraries against unmodified and non-immobilized protein targets. Angew. Chem. Int. Ed. 53, 10056–10059 (2014).

    Article  Google Scholar 

  83. Denton, K. E. & Krusemark, C. J. Crosslinking of DNA-linked ligands to target proteins for enrichment from DNA-encoded libraries. MedChemComm 7, 2020–2027 (2016).

    Article  Google Scholar 

  84. Santos, R. et al. A comprehensive map of molecular drug targets. Nat. Rev. Drug Discov. 16, 19–34 (2017).

    Article  Google Scholar 

  85. Brown, D. G. et al. Agonists and antagonists of protease-activated receptor 2 discovered within a DNA-encoded chemical library using mutational stabilization of the target. SLAS Discov. 23, 429–436 (2018).

    Article  Google Scholar 

  86. Cheng, R. K. Y. et al. Structural insight into allosteric modulation of protease-activated receptor 2. Nature 545, 112–115 (2017).

    Article  ADS  Google Scholar 

  87. Kollmann, C. S. et al. Application of encoded library technology (ELT) to a protein–protein interaction target: discovery of a potent class of integrin lymphocyte function-associated antigen 1 (LFA-1) antagonists. Bioorg. Med. Chem. 22, 2353–2365 (2014).

    Article  Google Scholar 

  88. Huang, Y. et al. Selection of DNA-encoded chemical libraries against endogenous membrane proteins on live cells. Nat. Chem. 13, 77–88 (2021). Novel technique to conduct a DECL selection against cell surface targets, without the requirement for target overexpression.

    Article  Google Scholar 

  89. Good, M. C., Zalatan, J. G. & Lim, W. A. Scaffold proteins: hubs for controlling the flow of cellular information. Science 332, 680–686 (2011).

    Article  ADS  Google Scholar 

  90. Zhao, G., Huang, Y., Zhou, Y., Li, Y. & Li, X. Future challenges with DNA-encoded chemical libraries in the drug discovery domain. Expert Opin. Drug Discov. 14, 735–753 (2019).

    Article  Google Scholar 

  91. McGregor, L. M., Jain, T. & Liu, D. R. Identification of ligand–target pairs from combined libraries of small molecules and unpurified protein targets in cell lysates. J. Am. Chem. Soc. 136, 3264–3270 (2014).

    Article  Google Scholar 

  92. Chan, A. I., McGregor, L. M., Jain, T. & Liu, D. R. Discovery of a covalent kinase inhibitor from a DNA-encoded small-molecule library×protein library selection. J. Am. Chem. Soc. 139, 10192–10195 (2017).

    Article  Google Scholar 

  93. Petersen, L. K. et al. Screening of DNA-encoded small molecule libraries inside a living cell. J. Am. Chem. Soc. 143, 2751–2756 (2021). Unique approach to conduct a DECL selection inside a living cell against unpurified target proteins.

    Article  Google Scholar 

  94. Satz, A. L., Dernick, G. & Zambaldo, C. Small Molecule Screening Cellular Assay Using Modified Beads. Patent No.WO/2020/212439 (2020).

  95. McCloskey, K. et al. Machine learning on DNA-encoded libraries: a new paradigm for hit finding. J. Med. Chem. 63, 8857–8866 (2020). First report of the interrogation of DECL selection data by machine learning.

    Article  Google Scholar 

  96. Li, K. et al. Solution-phase DNA-compatible pictet-spengler reaction aided by machine learning building block filtering. iScience 23, 101142 (2020).

    Article  ADS  Google Scholar 

  97. Disch, J. S. et al. Bispecific estrogen receptor α degraders incorporating novel binders identified using DNA-encoded chemical library screening. J. Med. Chem. 64, 5049–5066 (2021). Demonstration of how DECL can be applied to the discovery of protein degraders.

    Article  Google Scholar 

  98. An, Y.-L. et al. DNA compatible intermolecular wittig olefination for the construction of α, β-unsaturated carbonyl compounds. Org. Lett. 22, 3931–3935 (2020).

    Article  Google Scholar 

  99. Satz, A. L. in A Handbook for DNA-Encoded Chemistry 99–121 (John Wiley & Sons, 2014).

  100. Kölmel, D. K. et al. Employing photocatalysis for the design and preparation of DNA-encoded libraries: a case study. Chem. Rec. 21, 616–630 (2021).

    Article  Google Scholar 

  101. Jerry, C. J. et al. DNA barcoding a complete matrix of stereoisomeric small molecules. J. Am. Chem. Soc. 141, 10225–10235 (2019).

    Article  Google Scholar 

  102. Zambaldo, C., Geigle, S. N. & Satz, A. L. High-throughput solid-phase building block synthesis for DNA-encoded libraries. Org. Lett. 21, 9353–9357 (2019). First demonstration of how high-throughput chemistry can be used to expand the chemical space accessed by DECLs.

    Article  Google Scholar 

  103. Satz, A. L., Hochstrasser, R. & Petersen, A. C. Analysis of current DNA encoded library screening data indicates higher false negative rates for numerically larger libraries. ACS Comb. Sci. 19, 234–238 (2017). Discussion of how the numeric size of DECLs may impact their productivity.

    Article  Google Scholar 

  104. Satz, A. L. DNA encoded library selections and insights provided by computational simulations. ACS Chem. Biol. 10, 2237–2245 (2015).

    Article  Google Scholar 

  105. Flood, D. T. et al. RASS-enabled S/P−C and S−N bond formation for DEL synthesis. Angew. Chem. Int. Ed. 59, 7377–7383 (2020).

    Article  Google Scholar 

  106. Su, W. et al. Triaging of DNA-encoded library selection results by high-throughput resynthesis of DNA–conjugate and affinity selection mass spectrometry. Bioconjugate Chem. 32, 1001–1007 (2021).

    Article  Google Scholar 

  107. Seigal, B. A. et al. The discovery of macrocyclic XIAP antagonists from a DNA-programmed chemistry library, and their optimization to give lead compounds with in vivo antitumor activity. J. Med. Chem. 58, 2855–2861 (2015).

    Article  ADS  Google Scholar 

  108. Ishida, T. & Ciulli, A. E3 ligase ligands for PROTACs: how they were found and how to discover new ones. SLAS Discov. 26, 484–502 (2021).

    Article  Google Scholar 

  109. Nadin, A., Hattotuwagama, C. & Churcher, I. Lead-oriented synthesis: a new opportunity for synthetic chemistry. Angew. Chem. Int. Ed. 51, 1114–1122 (2012).

    Article  Google Scholar 

  110. Fitzgerald, P. R. & Paegel, B. M. DNA-encoded chemistry: drug discovery from a few good reactions. Chem. Rev. 121, 7155–7177 (2021).

    Article  Google Scholar 

  111. Hermann, J. C. et al. Metal impurities cause false positives in high-throughput screening campaigns. ACS Med. Chem. Lett. 4, 197–200 (2013).

    Article  Google Scholar 

  112. Cochrane, W. G. et al. Activity-based DNA-encoded library screening. ACS Comb. Sci. 21, 425–435 (2019). First report of a biochemical screen using a DECL.

    Article  Google Scholar 

  113. Stress, C. J., Sauter, B., Schneider, L. A., Sharpe, T. & Gillingham, D. A DNA-encoded chemical library incorporating elements of natural macrocycles. Angew. Chem. Int. Ed. 58, 9570–9574 (2019).

    Article  Google Scholar 

  114. Hunter, J. H. et al. High fidelity Suzuki–Miyaura coupling for the synthesis of DNA encoded libraries enabled by micelle forming surfactants. Bioconjug. Chem. 31, 149–155 (2020).

    Article  Google Scholar 

  115. Hansen, N., Andersen, J., Kristensen, O., Christensen, A. & Petersen, L. A method for screening of an in vitro display library within a cell. Patent No. WO/2020/152028 (2020).

  116. Rokicki, J. F., Nguyen, M. V., Vijayan, K. & Macconnell, A. B. Oligonucleotide encoded chemical libraries. Patent No. WO2019060830 (2019).

Download references

Author information

Authors and Affiliations

Authors

Contributions

Introduction (A.L.S.); Experimentation (A.B., A.G., G.O’D., J.S. and A.L.S.); Results (L.A.M., C.M. and A.L.S.); Applications (N.J.V.H., V.B.K.K. and D.M.); Reproducibility and data deposition (L.K., X.L. and A.L.S.); Limitations and optimizations (M.E.F., S.S. and A.L.S.); Outlook (A.L.S.). Overview of the Primer (A.L.S.).

Corresponding author

Correspondence to Alexander L. Satz.

Ethics declarations

Competing interests

A.B. is a co-founder of Serengen GmbH, a company that provides DNA-encoded library technology services. V.B.K.K. is an employee of Serengen GmbH. The other authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Methods Primers thanks Christoph Dumelin, Dennis Gillingham, Robert A. Goodnow, Miguel Pena Piñón and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Glossary

Public-knowledge-based rational design

Drug discovery starting with a publicly reported inhibitor, such as from the literature, patents or conference presentations.

Combinatorial chemistry

A process that comprises mixing and splitting of intermediate products, leading to exponential growth of product numbers.

Sticky end ligation of duplex DNA

Enzymatic joining of two duplex DNA fragments that contain short complementary single-stranded sequences, called overhangs.

Splint ligation of single-stranded DNA

Enzymatic joining of two single-stranded DNA fragments with the help of a third DNA strand that is partially complementary to both fragments.

Orthogonal functional groups

Functional groups that do not require protective groups when either of them is reacted in a synthesis route.

Lipinski rule of five

A set of empirically found physicochemical compound properties that are statistically associated with oral bioavailability.

Liquid chromatography–mass spectrometry

(LCMS). An instrument that allows for analysis of compound mixtures by separating them according to, for example, compound polarity and measuring product mass.

Synthon

A synonym for chemical building block.

Celite

Powdered, soft, siliceous sedimentary rock.

Phage-display technology

A technology that uses bacteriophages to connect peptides or proteins with the genetic information that encodes them.

Medicinal chemistry optimization

The optimization of molecules towards properties suitable for application in animal tests and clinical tests.

cLogP

The calculated logarithmic partition coefficient that indicates the portioning of a given molecule between water and octanol.

Pharmacophore

Description of molecular features that are required for recognition of a ligand by a biological target.

Multiparameter optimization scoring

A method for deriving a score for the relative importance of selectable physicochemical properties, aiding in prioritization of molecules.

AUC0–∞

Area under the curve (from zero to infinity), which represents the total drug exposure across time.

K d

Dissociation constant, the equilibrium constant of a non-covalent complex, for instance, formed by a drug-like molecule with its biological target molecule.

Poisson distribution

A mathematical equation used to calculate the probability that a certain number of discrete events will occur.

Confidence interval of 95%

Statistical estimate stating that there is a 95% chance that the unknown parameter will fall between the stated values.

Click reactions

Robust, largely condition-insensitive reactions with a high thermodynamic driving force and a broad substrate scope.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Satz, A.L., Brunschweiger, A., Flanagan, M.E. et al. DNA-encoded chemical libraries. Nat Rev Methods Primers 2, 3 (2022). https://doi.org/10.1038/s43586-021-00084-5

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s43586-021-00084-5

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing