General Covalent Inhibitor Library

Life Chemicals presents the General Covalent Inhibitor Library of over 10,900 compounds for covalent screening selected from the Life Chemicals HTS Compound Collection by specific structural moieties (functional groups), sometimes referred to as “warheads”, that are known to form covalent bonds with amino acid residues in binding sites of target proteins: Lys, Cys, Ser, Thr, Asp, Glu, and Tyr.

The following chemical classes and structural features were used for selection of possible covalent binding irreversible inhibitors:

  • β-lactams
  • Alkyl halides
  • Epoxides, aziridines
  • Michael acceptors:
    • α,β-unsaturated ketones, -nitriles, -esters;
    • maleimide-like compounds;
    • activated vinyl derivatives, etc.    
  • Cyanoacrylamides
  • Sulfonate esters
  • Sulfonyl fluorides
  • Thioles
  • Rodanides
  • Thiourea and thioketones
  • o-quinones
  • p-quinones
  • Ketales
  • Acetales
  • Disulfides
  • Terminal acetylenes
  • Sulfoalkenes

 

The final set of small-molecule screening compounds was obtained by applying the extended Rule of Five criteria:

  • MW 120 – 500
  • ClogP -0.4 – 5
  • Hb donor 0 – 5
  • Hb acceptor 0 – 10
  • Rotatable bonds ≤ 10
  • PSA ≤ 140 Å2

You can cherry-pick compounds or focus on a specific class of covalent modifiers. Separate focused sets of covalent binders targeting each of the indicated amino acid residues (Cysteine, Serine, Lysine, Tyrosine, Threonine) can be provided or request. Please, contact us at orders@lifechemicals.com for any details and quotations.

References:

  1. K. Zhu, K. W. Borrelli, J. Greenwood, T. Day, R. Abel, R. Farid, E. Harder J. Chem. Inf. Model., June 2014. doi: 10.1021/ci500118s
  2. D. T. Warshaviak, G. Golan, K. W. Borrelli, K. Zhu, O. Kalid J. Chem. Inf. Model., March 2014. doi: 10.1021/ci500175r
  3. Q. Liu, Y. Sabnis, Z. Zhao, T. Zhang, S. J. Buhrlage, L. H. Jones, N. S. Gray Cell Press: Chem. Biol., Vol. 20 (2),
  4. 2013, pp. 146–159.
  5. R. Mah, J. R. Thomas, C. M. Shafer Bioorg. Med. Chem. Lett., Vol. 24, 2014, pp. 33–39.
  6. D. S. Johnson, E. Weerapana, B. F. Cravatt Future Med. Chem., Vol. 2 (6), 2010, pp. 949–964.
  7. E. Weerapana, G. M. Simon, B. F. Cravatt Nature Chemical Bioogyl., Vol. 4, 2008, pp. 405–407.
  8. S. G. Kathman, Z. Xu, A. V. Statsyuk J. Med Chem., Vol. 57 (11), 2014, pp. 4969–4974.