Serine Protease Focused Library

Serine proteases are one of the most biologically important families of proteins that have been shown to play a multifarious role in various diseases. Their main function in humans is coordinating digestion function, however serine proteases are also involved in other processes such as inflammation, blood clotting, and the immune system in both prokaryotes and eukaryotes. Serine proteases have a distinctive structure, consisting of two beta-barrel domains that converge at the catalytic active site, and can be further categorised based on their substrate specificity as trypsin-like (positively charged residues Lys/Arg), elastase-like (small hydrophobic residues Ala, Val, Gly) or chymotrypsin-like (large hydrophobic residues Phe/Tyr/Trp). The enzymes are characterized by a catalytic triad of residues (Ser195, His57 and Asp102, chymotrypsin numbering system) that is responsible for amide bond hydrolysis.

The Life Chemicals Serine Protease Focused Library includes small molecule analogs of known serine proteinase inhibitors with experimentally determined activity. To design this library, a 2D similarity search method was used. A reference database of 26,000 biologically active compounds from assays related to serine proteases was collected using the data available from patents and literature publications. Life Chemicals Stock HTS collection was searched for compounds similar to the compounds from the reference database using MDL public keys and Tanimoto similarity cut-off of 85 %.

As a result, 2,998 compounds were selected for the Life Chemicals Serine Protease Focused Library, with their distinctive features being as follows:

  • No reactive and unstable molecules
  • Lilly MedChem Rules
  • PAINS filters families A, B, C applied

The list of targets used for the Library preparation is represented below:

  • Alpha-chymotrypsin
  • Cathepsin G
  • Coagulation factor X, XII
  • Dipeptidyl peptidase IV, VIII, IX, II, X, XII
  • Enteropeptidase
  • Epoxide hydratase
  • Epoxide hydrolase
  • Hepatitis C virus NS3 protease/helicase
  • Hepatitis C virus polyprotein
  • Human herpes virus 5 capsid protein P40
  • Kallikrein 7
  • Leukocyte elastase
  • Leukocyte proteinase 3
  • Matriptase
  • Membrane-bound transcription factor site-1 protease
  • Plasma kallikrein
  • Plasminogen
  • Prolyl endopeptidase
  • Seprase
  • Subtilisin-like serine protease
  • Thrombin
  • Tripeptidyl aminopeptidase
  • Trypsin
  • Tryptase beta-1
  • Urokinase-type plasminogen activator