Ligase Focused Screening Library

Ligases are enzymes that are capable of catalyzing the reaction of joining two large molecules by establishing a new chemical bond, generally with concomitant hydrolysis of a small chemical group on one of bulky molecules, or simply linking two compounds together [1]. They are classified under EC 6 primary class of enzymes and further divided into six subclasses known as ligases establishing carbon-oxygen bonds, carbon-sulfur bonds, carbon-nitrogen bonds, carbon-carbon bonds, phosphoric–ester bonds, and nitrogen–metal bonds [2].

These proteins are involved in various cellular pathways, including but not limited to protein trafficking, subcellular localization, innate immune response, viral infections, DNA damage responses and apoptosis [3]. But more often the ligase-system plays an important role in tumorigenesis and cancer development [4].

Life Chemicals has designed a Library of over 3,900 drug-like screening compounds that are small-molecule analogs of known ligase inhibitors with experimentally determined activity. Thus, The Library parameters make it an excellent source of new structures for drug discovery projects.

First, the reference set of 23,174 compounds with known ligase blocking activity was obtained from the CHEMBL database. The compounds have been filtered to keep only those possessing moderate and high activity against ligase targets, with further filtering narrowing down a set to 12,000 activity entries on 10,000 unique ligase modulators. A 2D fingerprint similarity search of the reference set has been done against the Life Chemicals HTS Compound Collection (Tanimoto > 0.85, max 50 analogs for a reference compound). In addition, molecules containing highly reactive groups have been removed from the final Library.

The search was performed against the following ligase enzyme targets (Fig. 1):

  • Acetyl-CoA carboxylase (type 1 and 2)
  • Acyl-CoA synthase
  • AMP-binding enzyme family protein
  • DNA ligase 1
  • Glutamine synthetase
  • NH(3)-dependent NAD(+) synthetase
  • Pantothenate synthetase
  • Methionyl-tRNA synthetase
  • Phenylalanyl-tRNA synthetase alpha chain
  • Lysine-, Proline-, Lysyl-, Cysteine-, Prolyl-tRNA synthetase
  • SUMO E1/E2 ligase
  • Transcription intermediary factor 1-alpha
  • E3 ubiquitin ligase MDM2
  • Tumor suppressor p53/oncoprotein Mdm2
  • E3 ubiquitin-protein ligase UHRF1
  • Inhibitor of apoptosis protein 3
  • p53-binding protein Mdm-2
  • Ubiquitin-conjugating enzyme E2 N
  • UDP-N-acetylmuramate-L-alanine ligase
  • UDP-N-acetylmuramoyl-alanine-D-glutamate ligase
  • UDP-N-acetylmuramoyl-tripeptide-D-alanyl-D-alanine ligase
  • UDP-N-acetylmuramoyl-L-alanyl-D-glutamate-2,6-diaminopimelate ligase
  • UDP-N-acetylmuramoylalanine-D-glutamyl-lysine-D-alanyl-D-alanine ligase

Compound distribution by general target classes within the Life Chemicals Ligases Focused Screening Library

Figure 1. Compound distribution by general target classes within the Life Chemicals Ligases Focused Screening Library

References:

  1. Nomenclature Committee of theInternational Union of Biochemistry and Molecular Biology(NC-IUBMB): The Enzyme List. Class 6 — Ligases. ExplorEnz database-2019. www.enzyme-database.org
  2. McCloskey CM, Liao JY, Bala S, Chaput JC. Ligase-Mediated Threose Nucleic Acid Synthesis on DNA Templates. ACS Synth Biol. 2019;8(2):282-286.
  3. Wang Y, Argiles-Castillo D, Kane EI, Zhou A, Spratt DE. HECT E3 ubiquitin ligases - emerging insights into their biological roles and disease relevance. J Cell Sci. 2020;133(7):jcs228072.
  4. Uchida C, Kitagawa M. RING-, HECT-, and RBR-type E3 Ubiquitin Ligases: Involvement in Human Cancer. Curr Cancer Drug Targets. 2016;16(2):157-174.
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