Covalent probes have traditionally targeted catalytic cysteine [1] or serine/threonine [2] residues located in active sites of enzymes, resulting in potent inhibition of their activity. However, recent advances have expanded the scope of covalent targeting, offering new opportunities for drug discovery and protein engineering. While cysteine's thiolate group is considered the most nucleophilic, other amino acid residues, such as lysine, can also be targeted. Lysine's abundance in proteins and its inherent nucleophilicity make it highly attractive for covalent modification under specific conditions. The key is to create a favorable microenvironment that enhances the nucleophilicity of this group or promotes tight binding of the reactive compound.
Our cheminformatics team has recently designed a novel Screening Set focused on lysine-specific covalent binders. It includes over 5,000 structurally diverse screening compounds selected from the Life Chemicals HTS Compound Collection and bearing the following promising lysine-focused electrophilic warheads [3]:
- carbonates
- heterocyclic aldehydes
- N-acetylacetamide
- heterocyclic aldehydes
- sulfonyl halides
- oxazinones
- ketoaldehydes
- sulfonyl heterocycles
- NO-dioxopyrrolidines
- vinyl sulfonamides
- thiazinones
- N-formyl heterocycles
These small molecules were also added to the General Covalent Screening Library containing potential covalent modifiers to target different amino acid residues (Cysteine, Serine, Lysine, Tyrosine) that can find their effective use in covalent screening projects in drug discovery.
The compound selection can be customized based on your requirements, cherry picking is available.
Please, contact us at orders@lifechemicals.com for any additional information and price quotations.
Figure. Eukaryotic translation initiation factor 4E (PDB ID: 6U09) binding site with a covalent inhibitor (F1957-0889). The lysine residue (K162), which is important for these interactions, is highlighted in orange.
Representative screening compounds from the Lysine-focused Covalent Inhibitor Library
Reference:
- Kato, D. et al. Activity-based probes that target diverse cysteine protease families. Nat. Chem. Biol. 1, 33–38 (2005).
- Bachovchin, D. A. & Cravatt, B. F. The pharmacological landscape and therapeutic potential of serine hydrolases. Nat. Rev. Drug Discov. 11, 52–68 (2012).
- Abbasov, M.E., Kavanagh, M.E., Ichu, TA. et al. A proteome-wide atlas of lysine-reactive chemistry. Nat. Chem. 13, 1081–1092 (2021). https://doi.org/10.1038/s41557-021-00765-4