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Serine focused Covalent Fragments

Special selection of Serine focused irreversible binders

1 836 compounds

An effective strategy for enhancing the potency and selectivity of initial active molecules is viacovalent bond formation with a nucleophilic residue that is quite specific and ideally absent from off-targets. Such 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. Covalent drugs and natural products are also well known. Serine hydrolases are one of the largest and most diverse classes of enzymes found in nature. These enzymes, which include lipases, esterases, thioesterases, amidases, peptidases and proteases, all utilize a base-activated serine nucleophile to cleave amide or ester (or thioester) bonds in substrates via a covalent acyl-enzyme intermediate.

We designed our Serine Focused Covalent Library based on combination of specific structural moieties (functional groups) reported to form covalent bonds with serine residue in binding sites of proteins, presence of drug like core and industry affiliated “Ro3” filters. The following functional groups able to form covalent bonds with proteins have used for compound selection:

Key features

  • Sulfonyl fluorides
  • Epoxides
  • β-Propiolactone; γ-butyrolactone; β-lactams
  • Boronic acids
  • Urea where both nitrogen atoms are in different rings (no isolated benzene rings), accounting N-carbamoyl-azoles.
  • 1,2-diazetidones ring enclosed.

Examples of the molecules

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