Covalent Inhibitor Library

Covalent inhibitors have many desirable features, including increased biochemical efficiency of target disruption, less sensitivity toward pharmacokinetic parameters and increased duration of action that outlasts pharmacokinetics of the compound. Safety concerns that must be mitigated include the lack of specificity and the potential immunogenicity of protein-inhibitor adduct(s).

Compounds from the Life Chemicals Covalent Inhibitors Library were selected by the presence of specific structural fragments (functional groups) that are known to form covalent bonds with amino acid residues in binding sites of target proteins: Lys, Cys, Ser, Asp, Glu and Tyr.

The following chemical classes and structural fragments were used for selection of possible covalent inhibitors:

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

The final set of compounds was obtained by applying an expanded Rule of Five criteria:

1. MW from 120 to 500
2. ClogP from - 0.4 to 5
3. Hb donor 0 – 5
4. Hb acceptor 0 – 10
5. rotatable bonds no more than 10
6. PSA no greater than 140 Ų

The Life Chemicals Covalent Inhibitors Library contains 6,400 compounds.

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. R. Mah, J. R. Thomas, C. M. Shafer Bioorg. Med. Chem. Lett., Vol. 24, 2014, pp. 33–39
5. D. S. Johnson, E. Weerapana, B. F. Cravatt Future Med. Chem., Vol. 2 (6), 2010, pp. 949–964.
6. E. Weerapana, G. M. Simon, B. F. Cravatt Nature Chemical Bioogyl., Vol. 4, 2008, pp. 405–407.
7. S. G. Kathman, Z. Xu, A. V. Statsyuk J. Med Chem., Vol. 57 (11), 2014, pp. 4969–4974