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Design Considerations in Constructing and Screening DNA-Encoded Libraries

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DNA-Encoded Libraries

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 40))

Abstract

Preparing a DNA-encoded chemical library platform is a major undertaking, which requires careful planning. Here we outline general design principles for DNA-encoded libraries on the levels of library topology, chemical reactions, and selection of building blocks. The effects of design parameters on the coverage of the chemical space by a DNA-encoded library and on the properties of encoded compounds are discussed.

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Abbreviations

AI:

Artificial intelligence

AS-MS:

Affinity selection mass spectrometry

BALI-MS:

Bead-assisted mass spectrometry

BB:

Building blocks

bRO5:

Beyond Lipinski’s rule of five

cLogP:

Calculated octanol/water partition coefficient

DEL:

DNA-encoded chemical library

ECFP:

Extended connectivity fingerprint

HTS:

High-throughput screening

LC-MS:

Liquid chromatography mass spectrometry

ML:

Machine learning

MW:

Molecular weight

PAINS:

Pan-assay interference compounds

PROTACs:

Proteolysis targeting chimeras

TMAP:

Tree MAP

References

  1. Dragovich PS, Haap W, Mulvihill MM, Plancher J, Stepan AF (2022) Small-molecule Lead-finding trends across the Roche and Genentech research organizations. J Med Chem 65(4):3606–3615

    Article  CAS  PubMed  Google Scholar 

  2. Gironda-Martinez A, Donckele EJ, Samain F, Neri D (2021) DNA-encoded chemical libraries: a comprehensive review with successful stories and future challenges. ACS Pharmacol Transl Sci 4(4):1265–1279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Goodnow Jr RA, Dumelin CE, Keefe AD (2017) DNA-encoded chemistry: enabling the deeper sampling of chemical space. Nat Rev Drug Discov 16(2):131–147

    Article  CAS  PubMed  Google Scholar 

  4. Yuen LH, Franzini RM (2017) Achievements, challenges, and opportunities in DNA-encoded library research: an academic point of view. Chembiochem 18(9):829–836

    Article  CAS  PubMed  Google Scholar 

  5. Yuen LH, Dana S, Liu Y, Bloom SI, Thorsell AG, Neri D, Donato AJ, Kireev D, Schuler H, Franzini RM (2019) A focused DNA-encoded chemical library for the discovery of inhibitors of NAD(+)-dependent enzymes. J Am Chem Soc 141(13):5169–5181

    Article  CAS  PubMed  Google Scholar 

  6. Bickerton GR, Paolini GV, Besnard J, Muresan S, Hopkins AL (2012) Quantifying the chemical beauty of drugs. Nat Chem 4(2):90–98

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hefti FF (2008) Requirements for a lead compound to become a clinical candidate. BMC Neurosci 9(Suppl 3):S7

    Article  PubMed  PubMed Central  Google Scholar 

  8. Franzini RM, Randolph C (2016) Chemical space of DNA-encoded libraries. J Med Chem 59(14):6629–6644

    Article  CAS  PubMed  Google Scholar 

  9. Shi B, Zhou Y, Huang Y, Zhang J, Li X (2017) Recent advances on the encoding and selection methods of DNA-encoded chemical library. Bioorg Med Chem Lett 27(3):361–369

    Article  CAS  PubMed  Google Scholar 

  10. Halford B (2017) How DNA-encoded libraries are revolutionizing drug discovery. Chem Eng News 95:25

    Google Scholar 

  11. Plais L, Scheuermann J (2022) Macrocyclic DNA-encoded chemical libraries: a historical perspective. RSC Chem Biol 3(1):7–17

    Article  CAS  PubMed  Google Scholar 

  12. Montoya AL, Glavatskikh M, Halverson BJ, Yuen LH, Schuler H, Kireev D, Franzini RM (manuscript submitted) Predicting lead compounds from DNA-encoded chemical libraries: understanding limitations of selection data, integrating pharmacophore building with docking, and discovery of Tankyrase 1 inhibitors

    Google Scholar 

  13. Satz AL (2018) What do you get from DNA-encoded libraries? ACS Med Chem Lett 9(5):408–410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Martin A, Nicolaou CA, Toledo MA (2020) Navigating the DNA encoded libraries chemical space. Commun Chem 3:127

    Article  CAS  Google Scholar 

  15. Franzini RM, Ekblad T, Zhong N, Wichert M, Decurtins W, Nauer A, Zimmermann M, Samain F, Scheuermann J, Brown PJ, Hall J, Graslund S, Schuler H, Neri D (2015) Identification of structure-activity relationships from screening a structurally compact DNA-encoded chemical library. Angew Chem Int Ed Engl 54(13):3927–3931

    Article  CAS  PubMed  Google Scholar 

  16. Samain F, Ekblad T, Mikutis G, Zhong N, Zimmermann M, Nauer A, Bajic D, Decurtins W, Scheuermann J, Brown PJ, Hall J, Graslund S, Schuler H, Neri D, Franzini RM (2015) Tankyrase 1 inhibitors with drug-like properties identified by screening a DNA-encoded chemical library. J Med Chem 58(12):5143–5149

    Article  CAS  PubMed  Google Scholar 

  17. Wang S, Denton KE, Hobbs KF, Weaver T, McFarlane JMB, Connelly KE, Gignac MC, Milosevich N, Hof F, Paci I, Musselman CA, Dykhuizen EC, Krusemark CJ (2020) Optimization of ligands using focused DNA-encoded libraries to develop a selective cell-permeable CBX8 Chromodomain inhibitor. ACS Chem Biol 15(1):112–131

    Article  CAS  PubMed  Google Scholar 

  18. Satz AL (2016) Simulated screens of DNA encoded libraries: the potential influence of chemical synthesis Fidelity on interpretation of structure-activity relationships. ACS Comb Sci 18(7):415–424

    Article  CAS  PubMed  Google Scholar 

  19. Satz AL, Hochstrasser R, Petersen AC (2017) Analysis of current DNA encoded library screening data indicates higher false negative rates for numerically larger libraries. ACS Comb Sci 19(4):234–238

    Article  CAS  PubMed  Google Scholar 

  20. McCloskey K, Sigel EA, Kearnes S, Xue L, Tian X, Moccia D, Gikunju D, Bazzaz S, Chan B, Clark MA, Cuozzo JW, Guie MA, Guilinger JP, Huguet C, Hupp CD, Keefe AD, Mulhern CJ, Zhang Y, Riley P (2020) Machine learning on DNA-encoded libraries: a new paradigm for hit finding. J Med Chem 63(16):8857–8866

    Article  CAS  PubMed  Google Scholar 

  21. Gorgulla C, Boeszoermenyi A, Wang ZF, Fischer PD, Coote PW, Padmanabha Das KM, Malets YS, Radchenko DS, Moroz YS, Scott DA, Fackeldey K, Hoffmann M, Iavniuk I, Wagner G, Arthanari H (2020) An open-source drug discovery platform enables ultra-large virtual screens. Nature 580(7805):663–668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Probst D, Reymond J-L (2020) Visualization of very large high-dimensional data sets as minimum spanning trees. J Cheminform 12:12

    Article  PubMed  PubMed Central  Google Scholar 

  23. Lemke M, Ravenscroft H, Rueb NJ, Kireev D, Ferraris D, Franzini RM (2020) Integrating DNA-encoded chemical libraries with virtual combinatorial library screening: optimizing a PARP10 inhibitor. Bioorg Med Chem Lett 30(19):127464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Clark MA, Acharya RA, Arico-Muendel CC, Belyanskaya SL, Benjamin DR, Carlson NR, Centrella PA, Chiu CH, Creaser SP, Cuozzo JW, Davie CP, Ding Y, Franklin GJ, Franzen KD, Gefter ML, Hale SP, Hansen NJ, Israel DI, Jiang J, Kavarana MJ, Kelley MS, Kollmann CS, Li F, Lind K, Mataruse S, Medeiros PF, Messer JA, Myers P, O'Keefe H, Oliff MC, Rise CE, Satz AL, Skinner SR, Svendsen JL, Tang L, van Vloten K, Wagner RW, Yao G, Zhao B, Morgan BA (2009) Design synthesis and selection of DNA-encoded small-molecule libraries. Nat Chem Biol 5(9):647–654

    Article  CAS  PubMed  Google Scholar 

  25. Mannoccia L, Zhang Y, Scheuermann J, Leimbacher M, De Bellis G, Rizzi E, Dumelin C, Melkko S, Neri D (2008) High-throughput sequencing allows the identification of binding molecules isolated from DNA-encoded chemical libraries. Proc Natl Acad Sci 105(46):17670–17675

    Article  Google Scholar 

  26. Wang X, Sun H, Liu J, Dai D, Zhang M, Zhou H, Zhong W, Lu X (2018) Ruthenium-Promoted C–H Activation Reactions between DNA-Conjugated Acrylamide and Aromatic Acids. Org Lett 20(16):4764–4768

    Article  CAS  PubMed  Google Scholar 

  27. Kölmel DK, Loach RP, Knauber T, Flanagan ME (2018) Employing photoredox catalysis for DNA-encoded chemistry: decarboxylative alkylation of α-amino acids. Chem Med Chem 13(20):2159–2165

    Article  PubMed  Google Scholar 

  28. Badir SO, Sim J, Zhang X, Dong W, Molander GA, Billings K, Csakai A (2020) Multifunctional building blocks compatible with photoredox-mediated alkylation for DNA-encoded library synthesis. Org Lett 22(3):1046–1051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kölmel DK, Ratnayake AS, Flanagan ME, Tsai M-H, Duan C, Song C (2020) Photocatalytic [2 + 2] cycloaddition in DNA-encoded chemistry. Org Lett 22(8):2908–2913

    Article  PubMed  Google Scholar 

  30. Thomas B, Lu X, Birmingham WR, Huang K, Both P, Reyes Martinez JE, Young RJ, Davie CP, Flitsch SL (2017) Application of biocatalysis to on-DNA carbohydrate library synthesis. Chem Bio Chem 18:858

    Article  CAS  PubMed  Google Scholar 

  31. MacConnell AB, McEnaney PJ, Cavett VJ, Paegel BM (2015) DNA-encoded solid-phase synthesis: encoding language design and complex oligomer library synthesis. ACS Comb Sci 17(9):518–534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kunig VBK, Ehrt C, Dömling A, Brunschweiger A (2019) Isocyanide multicomponent reactions on solid-phase-coupled DNA oligonucleotides for encoded library synthesis. Org Lett 21(18):7238–7243

    Article  CAS  PubMed  Google Scholar 

  33. Brown DG, Boström J (2016) Analysis of past and present synthetic methodologies on medicinal chemistry: where have all the new reactions gone? J Med Chem 59(10):4443–4458

    Article  CAS  PubMed  Google Scholar 

  34. Fair R, Walsh RT, Hupp CD (2021) The expanding reaction toolkit for DNA-encoded libraries. Bioorg Med Chem Lett 51:128339

    Article  CAS  PubMed  Google Scholar 

  35. Kalliokoski T (2015) Price-focused analysis of commercially available building blocks for combinatorial library synthesis. ACS Comb Sci 17(10):600–607

    Article  CAS  PubMed  Google Scholar 

  36. Zhang Y, Clark MA (2021) Design concepts for DNA-encoded library synthesis. Bioorg Med Chem 51:116189

    Article  Google Scholar 

  37. Zhu H, Flanagan ME, Stanton RV (2019) Designing DNA encoded libraries of diverse products in a focused property space. J Chem Inf Model 59:4645–4653

    Article  CAS  PubMed  Google Scholar 

  38. Lovering F, Bikker J, Humblet C (2009) Escape from flatland: increasing saturation as an approach to improving clinical success. J Med Chem 52(21):6752–6756

    Article  CAS  PubMed  Google Scholar 

  39. Caron G, Kihlberg J, Goetz G, Ratkova E, Poongavanam V, Ermondi G (2021) Steering new drug discovery campaigns: permeability, solubility, and physicochemical properties in the bRo5 chemical space. Med Chem Lett 12(1):13–23

    Article  CAS  Google Scholar 

  40. Doak BC, Over B, Giordanetto F, Kihlberg J (2014) Oral druggable space beyond the rule of 5: insights from drugs and clinical candidates. Chem Biol 21(9):1115–1142

    Article  CAS  PubMed  Google Scholar 

  41. DeGoey DA, Chen H, Cox PB, Wendt MD (2018) Beyond the rule of 5: lessons Learned from AbbVie’s drugs and compound collection. J Med Chem 61(7):2636–2651

    Article  CAS  PubMed  Google Scholar 

  42. Onda Y, Bassi G, Elsayed A, Ulrich F, Oehler S, Plais L, Scheuermann J, Neri D (2021) A DNA-encoded chemical library based on peptide macrocycles. Chem A Eur J 27:7160

    Article  CAS  Google Scholar 

  43. Koesema E, Roy A, Paciaroni NG, Coito C, Tokmina-Roszyk M, Kodadek T (2022) Synthesis and screening of a DNA-encoded library of non-peptidic macrocycles. Angew Chem Int Ed 61:e202116999

    Article  CAS  Google Scholar 

  44. Foley TL, Burchett W, Chen Q, Flanagan ME, Kapinos B, Li X, Montgomery JI, Ratnayake AS, Zhu H, Peakman M (2021) Selecting approaches for hit identification and increasing options by building the efficient discovery of actionable chemical matter from DNA-encoded libraries. SLAS Discov 26(2):263–280

    Article  CAS  PubMed  Google Scholar 

  45. Phelan JP, Lang SB, Sim J, Berritt S, Peat AJ, Billings K, Fan L, Molander GA (2019) Open-air alkylation reactions in photoredox-catalyzed DNA-encoded library synthesis. J Am Chem Soc 141(8):3723–3732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ratnayake AS, Flanagan ME, Foley TL, Smith JD, Johnson JG, Bellenger J, Montgomery JI, Paegel BM (2019) A solution phase platform to characterize chemical reaction compatibility with DNA-encoded chemical library synthesis. ACS Comb Sci 21(10):650–655

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Cuozzo JW, Clark MA, Keefe AD, Kohlmann A, Mulvihill M, Ni H, Renzetti LM, Resnicow DI, Ruebsam F, Sigel EA, Thomson HA, Wang C, Xie Z, Zhang Y (2020) Novel autotaxin inhibitor for the treatment of idiopathic pulmonary fibrosis: a clinical candidate discovered using DNA-encoded chemistry. J Med Chem 63(14):7840–7856

    Article  CAS  PubMed  Google Scholar 

  48. Dahlin JL, Nissink JWM, Strasser JM, Francis S, Higgins L, Zhou H, Zhang Z, Walters MA (2015) PAINS in the assay: chemical mechanisms of assay interference and promiscuous enzymatic inhibition observed during a sulfhydryl-scavenging HTS. J Med Chem 58(5):2091–2113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Baell JB, Holloway GA (2010) New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J Med Chem 53(7):2719–2740

    Article  CAS  PubMed  Google Scholar 

  50. Bolz SN, Adasme MF, Schroeder M (2021) Toward an understanding of pan-assay interference compounds and promiscuity: a structural perspective on binding modes. J Chem Inf Model 61(5):2248–2262

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors would like to acknowledge Matthew Clark and Anthony Keefe for their helpful comments.

Author information

Authors and Affiliations

  1. X-Chem, Inc., Waltham, MA, USA

    Ying Zhang

  2. Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT, USA

    Raphael M. Franzini

Authors
  1. Ying Zhang
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  2. Raphael M. Franzini
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Corresponding authors

Correspondence to Ying Zhang or Raphael M. Franzini .

Editor information

Editors and Affiliations

  1. Faculty of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany

    Andreas Brunschweiger

  2. Department of Pharmacology and Chemical Biology, Department of Pathology and Immunology, Center for Drug Discovery, Baylor College of Medicine, Houston, TX, USA

    Damian W. Young

Ethics declarations

Funding: Ying Zhang received no financial support to assist with the preparation of this manuscript. Raphael Franzini is supported by the National Institutes of Health (R35GM138335).

Declaration of Conflicting Interests: Ying Zhang is employed by X-Chem, Inc.; the research and authorship of this chapter were completed within the scope of the employment with X-Chem, Inc. Raphael Franzini is a scientific advisor for Leash Laboratories and ConfometRx.

Ethical approval: This Chapter does not contain any studies with human participants or animals performed by any of the authors.

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Zhang, Y., Franzini, R.M. (2022). Design Considerations in Constructing and Screening DNA-Encoded Libraries. In: Brunschweiger, A., Young, D.W. (eds) DNA-Encoded Libraries. Topics in Medicinal Chemistry, vol 40. Springer, Cham. https://doi.org/10.1007/7355_2022_147

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