Serine Focused Covalent Inhibitors Library

An effective strategy for enhancing the potency and selectivity of initial active molecules is via covalent bond formation with a nucleophilic residue that is specific to a target of interest and ideally showing no off-target interactions. Such covalent-acting chemical probes have increasingly been used in proteome-wide target identification and imaging as well as for finding inhibitors with high specificity among related enzymes and enzyme isoforms.

Life Chemicals has designed its Serine Focused Covalent Library on the basis of combination of specific structural fragments (functional groups) that were reported to form covalent bonds with serine residue in binding sites of proteins [1-5] and drug-like filters (Lipinski’s Rule of Five, Veber Rules, reactive groups and selected PAINS filters). Compounds with the following structure fragments were included into the Library:

  • Carbamates
  • Activated aliphatic nitriles (retro Michael acceptors)
  • Epoxides
  • β-propiolactones; γ-butyrolactones
  • β-lactams
  • Boronic acids
  • Aryl ureas (no isolated benzene ring)
  • Trifluoroacetamides
  • α-hydroxy ketones
  • α-ketoalkyl oxazoles
  • N-carbamoyl azoles
  • 1,2-diazetidones

The total number of compounds in the library: 1,700.

References

  1. Bachovchin D. A., Cravatt B. F. The pharmacological landscape and therapeutic potential of serine hydrolases. Nat. Rev. Drug Discov., 2012, 11, 52–68.
  2. Cognetta A. B., Niphakis M. J., Lee H. C., Martini M. L., Hulce J. J., Cravatt B. F. Selective N-Hydroxyhydantoin Carbamate Inhibitors of Mammalian Serine Hydrolases. Chem. Biol., 2015 Jun 25.
  3. Hoover H. S., Blankman J. L., Niessen S. Cravatt B. F. Selectivity of inhibitors of endocannabinoid biosynthesis evaluated by activity-based protein profiling. Bioorg. Med. Chem. Lett., 2008, 18, 5838–5841.
  4. Sgrignani J., Novati B., Colombo G., Grazioso G. Covalent docking of selected boron-based serine beta-lactamase inhibitors. J. Comput. Aided Mol. Des., 2015, 5, 441–50.
  5. Singh J., Petter R. C., Baillie T. A., Whitty, A. The resurgence of covalent drugs. Nature Rev. Drug Discov., 2011, 10, 307–317.