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 inhibitors. This kind of inhibition has many desirable features, including higher biochemical efficiency of target disruption, less 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, we’ve 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 fragments 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 Library comprises over 4,000 small-molecule compounds for covalent fragment screening efforts (Fig. 1-2).

Additionally, molecules with highly reactive electrophilic and nucleophilic groups (non-selective covalent binders), as well as compounds with non-drug-like cores, were discarded, using unwanted fragments and appropriate PAINS filters to produce the Advanced Subset of more than 2,800 compounds.

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

You can cherry-pick compounds or focus on a specific class of covalent modifiers.

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

Representative fragments with potential covalent inhibition activity

Figure 1. Representative compounds from the Covalent Fragment Library


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

Figure 2. Distribution of fragments by their covalent warheads in the Covalent Fragment Library (excluding Michael acceptors and other types)

References

  1. Mah R.; Thomas J. R.; Shafer C. M. Bioorg. Med. Chem. Lett. 2014, 24, 33–39.
  2. Johnson D. S.; Weerapana E.; Cravatt B. F. Future Med. Chem. 2010, 2 (6), 949–964.
  3. Weerapana E., Simon G., Cravatt B. F. Nature Chemical Bioogyl., Vol. 4, 2008, pp. 405–407.
  4. Liu Q. et. al. Chem. Biol., 2013, 20 (2), 146–159.
  5.  Kathman S.; Ziyang X.; Statsyk A. V. J. Med. Chem. 2014, 57 (11), 4969–4974. 
  6. Zhu K. et. al. J. Chem. Inf. Model. 2014, 54 (7), 1932-1940.
  7. Warshaviak D. T. et al. J. Chem. Inf. Model. 2014, 54 (7), 1941–1950
  8. Mah R.; Thomas J. R.; Shafer C. M. Bioorg. Med. Chem. Lett. 2014, 24, 33–39.
  9. Kathman SG, Statsyuk AV. Medchemcomm. 2016 Apr 1;7(4):576-585.
  10. Keeley A, Ábrányi-Balogh P, Keserű GM. Medchemcomm. 2018 Dec 10;10(2):263-267.