Cysteine Focused Covalent Inhibitor Library

The Cys-focused Screening Compound Library was created on the basis of specific structure moieties that could react reversibly or irreversibly with cysteine residues of a drug target. It contains over 2,200  potential covalent modifiers.

On the basis of literature data [1-8], we selected the most important functional groups that are known to target binding pockets of proteins through the formation of covalent bonds with cysteine amino acid residues. Michael acceptors are typical functionalities that are often introduced in structures of this type of covalent inhibitors as well as fragments, capable of nucleophilic displacement or addition.

Covalent inhibitors focused on Cys residue were selected from the Life Chemicals HTS Compound Collection, employing the following covalent warheads (Fig. 1):

  • α,β-unsaturated ketones
  • α-chloracetamides
  • activated acetylenes
  • acrylonitriles
  • acrylamides
  • epoxides
  • methyl vinylsulfones
  • phenylsulphonate esters
  • aminomethyl methyl acrylathes

The compounds were pre-filtered with the Rule of Five restrictions:

  • MW 150 - 500
  • ClogP -1 - 5
  • H-donors 0 - 5
  • H-acceptors 0 - 10
  • Rotatable bonds ≤ 10

Subsequently, machine learning methods (such as covalent fingerprints) and diversity filtering were applied to refine the selection of potential cysteine covalent binders for covalent screening efforts.

The compound selection can be customized based on your requirements, cherry-picking is available. Pre-plated set based on this Screening Library is also offered. For more details, please, consult our Pre-plated Focused Libraries. Please, contact us at orders@lifechemicals.com for any additional information and price quotations.

Covalent warheads distribution for compounds in the Cysteine-focused Covalent Inhibitor Library

 

Figure 1. Covalent warheads distribution for compounds in the Cysteine-focused Covalent Inhibitor Library

References

  1. S. G. Kathman, Z. Xu, A. V. Statsyk. J. Med. Chem., 2014, 57 (11), pp. 4969–4974.
  2. R. Mah, J. R. Thomas, C. M. Shafer Bioorg. Med. Chem. Lett., 2014, Vol. 24, pp. 33–39.
  3. Q. Liu, Y. Sabnis et. al. Cell Press: Chem. Biol., Vol. 20 (2), 2013, pp. 146–159.
  4. E. Weerapana, G.M. Simon, B.F. Cravatt Nature Chemical Bioogyl., Vol. 4, 2008, pp. 405–407.
  5. D. S. Johnson, E. Weerapana, B. F. Cravatt Future Med. Chem., Vol. 2 (6), 2010, pp. 949–964
  6. D. T. Warshaviak, G. Golan, K. W. Borrelli, K. Zhu, O. Kalid J. Chem. Inf. Model., 2014, 54 (7), pp. 1941–1950.
  7. K. Zhu, K. W. Borrelli, J. Greenwood, T. Day, R. Abel, R. Farid, E. Harder J. Chem. Inf. Model., 2014, 54 (7), pp. 1932 - 1940.
  8. Cohen MS, Zhang C, Shokat KM, Taunton J. Science, 2005, 308 (5726), pp. 1318–1321.
  9. Zhang T, Kwiatkowski N, Olson CM, Dixon-Clarke et al. Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors. Nat Chem Biol. 2016 Oct;12(10):876-84.
  10. He H, Jiang H, Chen Y, Ye J, Wang A, Wang C, et al. Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity. Nat Commun. 2018 Jun 29;9(1):2550.
  11. Lv Z, Yuan L, Atkison JH, Williams KM, Vega R, et al. Molecular mechanism of a covalent allosteric inhibitor of SUMO E1 activating enzyme. Nat Commun. 2018 Dec 4;9(1):5145.
  12. Mukherjee H, Grimster NP. Beyond cysteine: recent developments in the area of targeted covalent inhibition. Curr Opin Chem Biol. 2018 Jun;44:30-38.
  13. Bum-Erdene K, Zhou D, Gonzalez-Gutierrez G, Ghozayel MK, at al. Small-Molecule Covalent Modification of Conserved Cysteine Leads to Allosteric Inhibition of the TEAD⋅Yap Protein-Protein Interaction. Cell Chem Biol. 2019 Mar 21;26(3):378-389.e13.