Cysteine Focused Covalent Inhibitors Library

The Cys-focused compound library of potential covalent inhibitors was created on the basis of specific structure moieties that could react reversibly or irreversibly with cysteine residues of a drug target. On the basis of literature data [1-8], we selected the most important functional groups that are known to target binding pocket of proteins through formation of covalent bonds with Cys 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.

The following structural moieties were used for selection of possible covalent inhibitors focused on cysteine residue from the Life Chemicals Compounds Collection:

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

Compounds from the Life Chemicals Stock Collection were pre-filtered with the Rule of Five restrictions:

  • MW from 150 to 500
  • ClogP from -1 to 5
  • Hb donor: 0-5
  • Hb acceptor: 0-10
  • rotatable bonds: no more than 10

The total number of compounds in the selected set is 1,300.

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 MS1, Zhang C, Shokat KM, Taunton J. Science, 2005, 308 (5726), pp. 1318–1321.