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Covalent Fragment Library

In recent years, covalent chemical probes have become a hot research topic in drug discovery. The number of drug candidates with a covalent mechanism of action progressing through clinical trials or being approved by the FDA has grown significantly; around 30 % of the marketed drugs are covalent binders. This kind of irreversible inhibition has many desirable features, including higher biochemical efficiency of target disruption, lower sensitivity toward pharmacokinetic parameters, and increased duration of action that outlasts the pharmacokinetics of the compound [1].

The design of selective covalent irreversible inhibitors is conceptually very attractive, but in practice hard to achieve. That is because it is challenging to strike the right balance of molecular properties between reactivity and selectivity [2-4].

Taking into account a growing interest and widespread use of fragment-based drug discovery (FBDD), we have designed an exclusive collection of covalent inhibitor fragments based on the Life Chemicals HTS Compound Collection. Initially, all the compounds were filtered according to the Rule of Three criteria. After that, a preliminary set of covalent modifiers was created by singling out compounds with specific structural fragments (functional groups, warheads) [4-8] that are known to form covalent bonds with amino acid residues in binding sites of targeted proteins, e.g., Lys, Cys, Ser, His and Tyr.

The resulting Covalent Fragment Library comprises around 6,200 small-molecule compounds for covalent fragment screening (Fig. 1-2).

Focused sets of screening compounds targeting each of the indicated amino acid residues (Cysteine, Lysine, Serine, Histidine, Threonine) can be provided on request.

The following chemical classes and structural moieties were used for arraying potential covalent inhibitors:

  • Acrylamides
  • Acrylonitriles
  • Aliphatic thiols
  • Aromatic thiols
  • Ketals
  • Maleimides and related compounds
  • Sulfonate esters
  • Terminal acetylenes
  • Thioureas and thiones
  • Vinyl sulfones
  • Vinyl sulfonamides
  • Michael acceptors and other types


Distribution of fragments by their covalent warheads in the Covalent Fragment Library

Figure 1. Distribution of fragments by their covalent warheads in the Covalent Fragment Library

In addition, we have designed a Diversity Screening Set of 960 covalently binding fragments to provide the most-promising structurally diverse screening compounds in a convenient manner. These covalent fragment-like molecules possess a wide range of chemical structure dissimilarity and are compliant with in-house MedChem and PAINS structural filters [6-7].

The compound selection can be customized based on your requirements, cherry picking is available.

Please, contact us at orders@lifechemicals.com for any additional information and price quotations.

For a pre plated set based on this Screening Library, please, go over our Pre-plated Fragment Screening Sets.

Further exploring our related products will make your search even more rewarding:
 

Representative compounds from the Covalent Fragment Library

References

  1. Ghosh AK, Samanta I, Mondal A, Liu WR. Covalent Inhibition in Drug Discovery. ChemMedChem. 2019 May 6;14(9):889-906. doi: 10.1002/cmdc.201900107.
  2. Narayanan A, Jones LH. Sulfonyl fluorides as privileged warheads in chemical biology. Chem Sci. 2015 May 1;6(5):2650-2659. doi: 10.1039/c5sc00408j.
  3. Zhang H, Jiang W, Chatterjee P, Luo Y. Ranking Reversible Covalent Drugs: From Free Energy Perturbation to Fragment Docking. J Chem Inf Model. 2019;59(5):2093-2102. doi:10.1021/acs.jcim.8b00959
  4. Tuley A, Fast W. The Taxonomy of Covalent Inhibitors. Biochemistry. 2018;57(24):3326-3337. doi:10.1021/acs.biochem.8b00315
  5. Cywin CL, Firestone RA, McNeil DW, Grygon CA, Crane KM, White DM, Kinkade PR, Hopkins JL, Davidson W, Labadia ME, Wildeson J, Morelock MM, Peterson JD, Raymond EL, Brown ML, Spero DM. The design of potent hydrazones and disulfides as cathepsin S inhibitors. Bioorg Med Chem. 2003 Mar 6;11(5):733-40. doi: 10.1016/s0968-0896(02)00468-6.
  6. Book: Progress in Medicinal Chemistry
  7. Book: Annual Report on Medicinal Chemistry series. The Design of Covalent-Based Inhibitors
  8. Ghosh AK, Brindisi M. Organic carbamates in drug design and medicinal chemistry. J Med Chem. 2015;58(7):2895-2940. doi:10.1021/jm501371s
  9. Du H, Gao J, Weng G, et al. CovalentInDB: a comprehensive database facilitating the discovery of covalent inhibitors. Nucleic Acids Res. 2021;49(D1):D1122-D1129. doi:10.1093/nar/gkaa876
  10. Mah R.; Thomas J. R.; Shafer C. M. Bioorg. Med. Chem. Lett. 2014, 24, 33–39.
  11. Johnson D. S.; Weerapana E.; Cravatt B. F. Future Med. Chem. 2010, 2 (6), 949–964.
  12. Weerapana E., Simon G., Cravatt B. F. Nature Chemical Bioogyl., Vol. 4, 2008, pp. 405–407.
  13. Liu Q. et. al. Chem. Biol., 2013, 20 (2), 146–159.
  14.  Kathman S.; Ziyang X.; Statsyk A. V. J. Med. Chem. 2014, 57 (11), 4969–4974.
  15. Zhu K. et. al. J. Chem. Inf. Model. 2014, 54 (7), 1932-1940.
  16. Warshaviak D. T. et al. J. Chem. Inf. Model. 2014, 54 (7), 1941–1950
  17. Mah R.; Thomas J. R.; Shafer C. M. Bioorg. Med. Chem. Lett. 2014, 24, 33–39.
  18. Kathman SG, Statsyuk AV. Medchemcomm. 2016 Apr 1;7(4):576-585.
  19. Keeley A, Ábrányi-Balogh P, Keserű GM. Medchemcomm. 2018 Dec 10;10(2):263-267.
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