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:
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| Figure 1. Compound distribution by different chemical classes within the Library |
References:
- Tuley A, Fast W. The Taxonomy of Covalent Inhibitors. Biochemistry. 2018;57(24):3326-3337.
- 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.
- Singh J., Petter R. C., Baillie T. A., Whitty, A. The resurgence of covalent drugs. Nature Rev. Drug Discov., 2011, 10, 307–317.
- 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.
- Bachovchin D. A., Cravatt B. F. The pharmacological landscape and therapeutic potential of serine hydrolases. Nat. Rev. Drug Discov., 2012, 11, 52–68.
- 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.
- 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.