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Cysteine focused Covalent Fragments

Sharp-focused library of compounds able to form reversible and irreversible covalent bonds with Cys residue

3 225 compounds

The approach used to design our Cysteine focused fragments set is based on a deep and careful analysis of literature data on Cys reactivity as well as reactivity of aliphatic thiol groups with similar nucleophilicity. Specific structure moieties reported to react reversibly or irreversibly with Cysteine were collected from the literature and analyzed. We have selected most important functional groups that in the same time are not highly reactive to act as non-selective binders. When selecting a fragment, the reactivity of the “workheads” was taken into account at temperature range from room up to 40°C, as well as corresponding pH range.

Careful substructure search with exclusion of simple reagent were applied to the Enamine stock Collection. Resulted set of compounds was then considered to avoid PAINS cores and other non-drug-like moieties. Finally, after manual inspection of selected compounds the dataset of 1 000 molecules was obtained.

Selected covalent warheads

  • Acrylamides and their analogues
  • α , β-Unsaturated sulfones and sulfonamides
  • Activated terminal acetylenes
  • Activated cyano groups
    (e.g., 2-cyanopyridines, 2-cyanopyrimidines, 4-cyanopyridines)
  • Aliphatic thiols
  • Epoxides, lactones, lactams
  • Sulfonyl fluorides

Examples of the molecules

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