Serine focused Covalent Fragments

Special selection of Serine focused irreversible binders

1 800 compounds

The covalent bond formation with a target protein is an effective strategy for enhancing potency and selectivity of initial active molecules. Different specific covalent-acting chemical probes have increasingly been used in proteome-wide target identification and imaging and for finding inhibitors with high specificity among related enzymes and enzyme isoforms. Significant number of known covalent drugs and natural products have approved efficacy of such approach in drug discovery.

The Serine hydrolase enzyme family is one of the largest and most diverse protein classes, including proteases, lipases, esterases, thioesterases, amidases and peptidases. All these enzymes utilize a base-activated serine residue cleavage of amide (ester or thioester) bonds in substrates via a covalent acyl-enzyme intermediate.

We have carefully designed our Serine Focused Covalent Fragment Library based on a combination of specific reactive moieties, reported to form covalent bonds with serine residue, and presence of a drug-like, MedChem friendly core in a molecule. The library has also been shaped with Ro3 criteria to meet all requirements of FBDD.

The following functional groups, previously reported to form covalent bonds with proteins, have been used for a compound selection:

  • Sulfonyl fluorides
  • Epoxides
  • β-Propiolactone; γ-butyrolactone; β-lactams
  • Boronic acids
  • Aryl ureas with one nitrogen being in aliphatic ring (e.g. piperidines, piperazines)

Examples of the molecules


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