Serine Focused Covalent Inhibitor 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 [1-3]. Such covalent-binding 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 [4]. 

Life Chemicals has designed its Serine Focused Covalent Library on the basis of a combination of specific structural fragments (functional groups or covalent “warheads”) that were reported to form covalent bonds with a serine residue in binding sites of proteins [5-7] and drug-like filters.

Over 2,700 small-molecule screening compounds with the following structure fragments were included in the Library:

  • Haloalkane
  • Hydroxy ketones
  • Halogens
  • Acetylenes
  • Lactams
  • Hydrozylamines
  • Boronic acids
 
  • Carbamates
  • Lactones
  • Michael acceptors
  • Piperazines
  • Piperidines
  • Ureas

 

Compound distribution by different chemical classes within the Library 
 Figure 1. Compound distribution by different chemical classes within the Library

 

References:

  1. Tuley A, Fast W. The Taxonomy of Covalent Inhibitors. Biochemistry. 2018;57(24):3326-3337.
  2. 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.
  3. Singh J., Petter R. C., Baillie T. A., Whitty, A. The resurgence of covalent drugs. Nature Rev. Drug Discov., 2011, 10, 307–317.
  4. Huang F, Zhang B, Zhou S, Zhao X, Bian C, Wei Y. Chemical proteomics: terra incognita for novel drug target profiling. Chin J Cancer. 2012;31(11):507-518.
  5. Bachovchin D. A., Cravatt B. F. The pharmacological landscape and therapeutic potential of serine hydrolases. Nat. Rev. Drug Discov., 2012, 11, 52–68.
  6. 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.
  7. 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.
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