Assessment of the Commercially Available Chemical Space for Using in the 19F NMR FAXS Method: a Enamine Ltd. Case

Authors

DOI:

https://doi.org/10.24959/ophcj.23.281281

Keywords:

fluorinated fragments, fragment-based drug design, 19F NMR, FAXS method, chemoinformatics, chemical space analysis of compounds

Abstract

Aim. To analyze commercially available fluorine containing compounds for the possibility of their use in the 19F NMR FAXS method.
Materials and methods. The selection of fluorine-containing fragments for the study was performed using 3.9 million instock screening compounds and 248,000 in-stock building-blocks from Enamine Ltd library. The selection and classification of the compounds was carried out using the DataWarrior and KNIME software. The Fluorinated Fragments library of Enamine Ltd. containing 6377 compounds, was also analyzed. To analyze the abovementioned sets of substances, the multistep workflows specially designed were used.
Results and discussion. As a result of applying the workflow developed to the compound sets (both screening compounds and building blocks), 13 800 compounds were selected and further classified according to the presence of one out of 12 fluorine-containing groups. The Fluorinated Fragments library was also subjected to a similar workflow. For the latter, 8 out of 12 fluorine-containing groups were identified. Additionally, experimental 19F NMR chemical shift values for Fluorinated Fragments library compounds spectra were analyzed. It has been found that some structural classes have areas of chemical shifts intersection. On the other hand, the ranges from –40 to –60 ppm and beyond –160 ppm are free from any group of compounds from the library analyzed.
Conclusions. The analysis has shown that commercially available fluorine-containing fragments do not satisfy the needs of the 19F NMR FAXS method, and further expansion of the chemical space of fluorine-containing compounds by increasing their diversity is required.

Supporting Agency

  • The authors received no specific funding for this work

Downloads

Download data is not yet available.

References

  1. Menaa, F.; Menaa, B.; Sharts, O. Importance of Fluorine and Fluorocarbons in Medicinal Chemistry and Oncology. J. Mol. Pharm. Org. Process Res. 2013. 1, 104. https://doi.org/10.4172/2329-9053.1000104.
  2. Bassetto, M.; Ferla, S.; Pertusati, F. Polyfluorinated Groups in Medicinal Chemistry. Future Medicinal Chemistry 2015, 7, 527–546. https://doi.org/10.4155/fmc.15.5.
    |
  3. Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. Applications of Fluorine in Medicinal Chemistry. Journal of Medicinal Chemistry 2015, 58, 8315–8359. https://doi.org/10.1021/acs.jmedchem.5b00258.
    |
  4. Swallow, S., Chapter Two - Fluorine in Medicinal Chemistry. In Progress in Medicinal Chemistry, Lawton, G.; Witty, D. R., Eds. Elsevier: 2015; Vol. 54, pp 65-133. https://doi.org/10.1016/bs.pmch.2014.11.001.
    |
  5. Westwell, A. D., Ed. Fluorinated Pharmaceuticals: Advances in Medicinal Chemistry; Future Science Ltd, 2015. https://doi.org/10.4155/9781909453968.
  6. Neil, E.; Marsh, G. Towards the Nonstick Egg: Designing Fluorous Proteins. Chemistry & Biology 2000, 7, R153–R157. https://doi.org/10.1016/s1074-5521(00)00139-3.
  7. Strunecká, A.; Patočka, J.; Connett, P. Fluorine in Medicine. Journal of Applied Biomedicine 2004, 2, 141–150. https://doi.org/10.32725/jab.2004.017.
  8. Dietschreit, J. C. B.; Wagner, A.; Le, T. A.; Klein, P.; Schindelin, H.; Opatz, T.; Engels, B.; Hellmich, U. A.; Ochsenfeld, C. Predicting 19F NMR Chemical Shifts: A Combined Computational and Experimental Study of a Trypanosomal Oxidoreductase–Inhibitor Complex. Angewandte Chemie International Edition 2020, 59, 12669–12673. https://doi.org/10.1002/anie.202000539.
  9. Yamaguchi, H. Fluorine in Medicine. In Perfluoroalkyl Substances; Améduri, B., Ed. The Royal Society of Chemistry: 2022; pp 440 - 458. https://doi.org/10.1039/9781839167591-00440.
  10. Vulpetti, A.; Lingel, A.; Dalvit, C.; Schiering, N.; Oberer, L.; Henry, C.; Lu, Y. Efficient Screening of Target‐Specific Selected Compounds in Mixtures by 19F NMR Binding Assay with Predicted 19F NMR Chemical Shifts. ChemMedChem 2022, 17, e202200163. https://doi.org/10.1002/cmdc.202200163.
    |
  11. Dalvit, C.; Vulpetti, A. Ligand-Based Fluorine NMR Screening: Principles and Applications in Drug Discovery Projects. Journal of Medicinal Chemistry 2018, 62, 2218–2244. https://doi.org/10.1021/acs.jmedchem.8b01210.
    |
  12. Norton, R.; Leung, E.; Chandrashekaran, I.; MacRaild, C. Applications of 19F-NMR in Fragment-Based Drug Discovery. Molecules 2016, 21, 860. https://doi.org/10.3390/molecules21070860.
    |
  13. Congreve, M.; Chessari, G.; Tisi, D.; Woodhead, A. J. Recent Developments in Fragment-Based Drug Discovery. Journal of Medicinal Chemistry 2008, 51, 3661–3680. https://doi.org/10.1021/jm8000373.
    |
  14. Erlanson, D. A.; Fesik, S. W.; Hubbard, R. E.; Jahnke, W.; Jhoti, H. Twenty Years on: The Impact of Fragments on Drug Discovery. Nat. Rev. Drug Discovery 2016, 15, 605–619. https://doi.org/10.1038/nrd.2016.109.
    |
  15. Kang, C. 19F-NMR in Target-Based Drug Discovery. Current Medicinal Chemistry 2019, 26, 4964–4983. https://doi.org/10.2174/0929867326666190610160534.
    |
  16. Jordan, J. B.; Poppe, L.; Xia, X.; Cheng, A. C.; Sun, Y.; Michelsen, K.; Eastwood, H.; Schnier, P. D.; Nixey, T.; Zhong, W. Fragment Based Drug Discovery: Practical Implementation Based on 19F NMR Spectroscopy. Journal of Medicinal Chemistry 2012, 55, 678–687. https://doi.org/10.1021/jm201441k.
    |
  17. Renaud, J.-P.; Chung, C.; Danielson, U. H.; Egner, U.; Hennig, M.; Hubbard, R. E.; Nar, H. Biophysics in Drug Discovery: Impact, Challenges and Opportunities. Nat. Rev. Drug Discovery 2016, 15, 679–698. https://doi.org/10.1038/nrd.2016.123.
    |
  18. Enamine Ltd. https://enamine.net/ (accessed Mar 10, 2023).
  19. Volochnyuk, D. M.; Ryabukhin, S. V.; Moroz, Y. S.; Savych, O.; Chuprina, A.; Horvath, D.; Zabolotna, Y.; Varnek, A.; Judd, D. B. Evolution of Commercially Available Compounds for HTS. Drug Discovery Today 2019, 24, 390–402. https://doi.org/10.1016/j.drudis.2018.10.016.
    |
  20. Enamine Ltd. Screening Collection. https://enamine.net/compound-collections/screening-collection (accessed Mar 11, 2023).
  21. Enamine Ltd. BUILDING BLOCKS CATALOG. https://enamine.net/building-blocks/building-blocks-catalog (accessed Mar 11, 2023).
  22. Sander, T.; Freyss, J.; von Korff, M.; Rufener, C. DataWarrior: An Open-Source Program For Chemistry Aware Data Visualization And Analysis. Journal of Chemical Information and Modeling 2015, 55, 460–473. https://doi.org/10.1021/ci500588j.
    |
  23. Berthold, M. R.; Cebron, N.; Dill, F.; Gabriel, T. R.; Kötter, T.; Meinl, T.; Ohl, P.; Thiel, K.; Wiswedel, B. KNIME – the Konstanz Information Miner. ACM SIGKDD Explorations Newsletter 2009, 11, 26–31. https://doi.org/10.1145/1656274.1656280.
  24. Kralj, S.; Jukič, M.; Bren, U. Comparative Analyses of Medicinal Chemistry and Cheminformatics Filters with Accessible Implementation in Konstanz Information Miner (KNIME). International Journal of Molecular Sciences 2022, 23, 5727. https://doi.org/10.3390/ijms23105727.
  25. KNIME AG. KNIME v.4.3.0; Zurich, Switzerland, 2022.
  26. Chessari, G.; Woodhead, A. J. From Fragment to Clinical Candidate – a Historical Perspective. Drug Discovery Today 2009, 14, 668–675. https://doi.org/10.1016/j.drudis.2009.04.007.
    |
  27. Congreve, M.; Carr, R.; Murray, C.; Jhoti, H. A “Rule of Three” for Fragment-Based Lead Discovery? Drug Discovery Today 2003, 8, 876–877. https://doi.org/10.1016/s1359-6446(03)02831-9.
    |
  28. Jhoti, H.; Williams, G.; Rees, D. C.; Murray, C. W. The “Rule of Three” for Fragment-Based Drug Discovery: Where Are We Now? Nat. Rev. Drug Discovery, 2013, 12, 644–644. https://doi.org/10.1038/nrd3926-c1.
    |
  29. Walters, W. P.; Murcko, M. A. Prediction of “Drug-Likeness”. Advanced Drug Delivery Reviews 2002, 54, 255–271. https://doi.org/10.1016/s0169-409x(02)00003-0.
    |
  30. O’Hagan, D. Fluorine in Health Care: Organofluorine Containing Blockbuster Drugs. Journal of Fluorine Chemistry 2010, 131, 1071–1081. https://doi.org/10.1016/j.jfluchem.2010.03.003.
  31. Volochnyuk, D. M.; Grygorenko, O. O.; Gorlova, A. O. Fluorine-Containing Diazines in Medicinal Chemistry and Agrochemistry. In Fluorine in Heterocyclic Chemistry Volume 2: 6-Membered Heterocycles; Nenajdenko, V., Ed.; Springer International Publishing: Cham, 2014; pp 577-672. https://doi.org/10.1007/978-3-319-04435-4_7.
  32. Ojima, I. Strategic Incorporation of Fluorine into Taxoid Anticancer Agents for Medicinal Chemistry and Chemical Biology Studies. Journal of Fluorine Chemistry 2017, 198, 10–23. https://doi.org/10.1016/j.jfluchem.2016.12.016.
  33. Haranahalli, K.; Honda, T.; Ojima, I. Recent Progress in the Strategic Incorporation of Fluorine into Medicinally Active Compounds. Journal of Fluorine Chemistry 2019, 217, 29–40. https://doi.org/10.1016/j.jfluchem.2018.11.002.
  34. Al-Harthy, T.; Zoghaib, W.; Abdel-Jalil, R. Importance of Fluorine in Benzazole Compounds. Molecules 2020, 25, 4677. https://doi.org/10.3390/molecules25204677.
    |
  35. Inoue, M.; Sumii, Y.; Shibata, N. Contribution of Organofluoride Compounds to Pharmaceuticals. ACS Omega 2020, 5, 10633–10640. https://doi.org/10.1021/acsomega.0c00830.
  36. Zhang, C. Fluorine in Medicinal Chemistry: In Perspective to COVID-19. ACS Omega 2022, 7, 18206–18212. https://doi.org/10.1021/acsomega.2c01121.
  37. DAYLIGHT, Chemical Information Systems Inc. SMARTS - A Language for Describing Molecular Patterns https://www.daylight.com/dayhtml/doc/theory/theory.smarts.html (accessed Mar 12, 2023).
  38. Zabolotna, Y.; Volochnyuk, D. M.; Ryabukhin, S. V.; Gavrylenko, K.; Horvath, D.; Klimchuk, O.; Oksiuta, O.; Marcou, G.; Varnek, A. SynthI: A New Open-Source Tool for Synthon-Based Library Design. Journal of Chemical Information and Modeling 2021, 62, 2151–2163. https://doi.org/10.1021/acs.jcim.1c00754.
    |
  39. Zabolotna, Y.; Volochnyuk, D. M.; Ryabukhin, S. V.; Horvath, D.; Gavrilenko, K. S.; Marcou, G.; Moroz, Y. S.; Oksiuta, O.; Varnek, A. A Close-up Look at the Chemical Space of Commercially Available Building Blocks for Medicinal Chemistry. Journal of Chemical Information and Modeling 2021, 62, 2171–2185. https://doi.org/10.1021/acs.jcim.1c00811.
    |
  40. Oksiuta, O. V.; Pashenko, A. E.; Smalii, R. V.; Volochnyuk, D. M.; Ryabukhin, S. V. Heterocyclization vs Coupling Reactions: A DNA-Encoded Libraries Case. Journal of Organic and Pharmaceutical Chemistry 2023, 21, 3–19. https://doi.org/10.24959/ophcj.23.275133.
  41. Enamine Ltd. Fluorinated Fragment Library. https://enamine.net/compound-libraries/fragment-libraries/fluorinated-fragment-library (March 2023).

Downloads

Additional Files

Published

2023-08-30

How to Cite

(1)
Oksiuta , O. V.; Filatov, Y. I. Assessment of the Commercially Available Chemical Space for Using in the 19F NMR FAXS Method: A Enamine Ltd. Case. J. Org. Pharm. Chem. 2023, 21, 21-28.

Issue

Vol. 21 No. 2 (2023)

Section

Original Researches

License

Copyright (c) 2023 National University of Pharmacy

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Authors publishing their works in the Journal of Organic and Pharmaceutical Chemistry agree with the following terms:

1. Authors retain copyright and grant the journal the right of the first publication of the work under Creative Commons Attribution License allowing everyone to distribute and re-use the published material if proper citation of the original publication is given.

2. Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal’s published version of the work (e.g., post it to an institutional repository or publish it in a book) providing proper citation of the original publication.

3. Authors are permitted and encouraged to post their work online (e.g. in institutional repositories or on authors’ personal websites) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (see The Effect of Open Access).