Ligases are enzymes that are capable of catalyzing the reaction of joining (ligation) 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 as EC 6 in the EC number classification 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]. Growing evidence has shown that the ligase-system plays an important role in tumorigenesis and cancer development [4].
Addressing the ligase related R&D challenges, Life Chemicals has designed a Screening Library of over 5,500 drug-like compounds that are small-molecule analogs of known ligase inhibitors with experimentally determined activity.
The compound selection can be customized based on your requirements, cherry picking is available.
Please, contact us at orders@lifechemicals.com for any additional information and price quotations.
Compound selection
To start, the reference set of over 23,000 compounds with known ligase-blocking activity was obtained from the CHEMBL database. The compounds were filtered to retain only those with moderate and high activity against ligase targets, with further filtering narrowing the set to 12,000 activity entries across 10,000 unique ligase modulators.
Then, a 2D fingerprint similarity search of the reference set was performed against the Life Chemicals HTS Compound Collection (Tanimoto > 0.85, max 50 analogs for a reference compound). In addition, molecules containing highly reactive groups were removed from the final Screening Library, making it an excellent source of new chemical structures for ligase-focused drug discovery projects.
The search was performed against the following ligase enzyme targets (Fig. 1):
- Proline-tRNA ligase
- Lysine-tRNA ligase
- Ubiquitin-conjugating enzyme E2 N
- Tumour suppressor p53/oncoprotein Mdm2
- E3 ubiquitin-protein ligase TRIM33
- E3 ubiquitin-protein ligase UHRF1
- Acetyl-CoA carboxylase
- Lysine--tRNA ligase
- Inhibitor of apoptosis protein 3
- Acetyl-CoA carboxylase 2
- MDM2-MDMX
- p53-binding protein Mdm-2
- Pantothenate synthetase
- Acyl-CoA synthase
- Prolyl-tRNA synthetase
- Methionyl-tRNA synthetase
- Acetyl-CoA carboxylase 2
- Phenylalanyl-tRNA synthetase alpha chain
- SUMO E1/E2
- DNA ligase 1
- Proline--tRNA ligase
- Transcription intermediary factor 1-alpha
- Cysteine--tRNA ligase, cytoplasmic
- UDP-N-acetylmuramoyl-tripeptide--D-alanyl-D-alanine ligase
- E3 ubiquitin-protein ligase
- E3 ubiquitin-protein ligase ZFP91
- Lysyl-tRNA synthetase
- E3 ubiquitin-protein ligase NEDD4
- E3 ubiquitin-protein ligase Praja-1 or NEDD4
- NH(3)-dependent NAD(+) synthetase
- UDP-N-acetylmuramoylalanine-D-glutamyl-lysine-D-alanyl-D-alanine ligase
Figure 1. Compound distribution by general target classes within the Life Chemicals Ligases Focused Screening Library
Representative compounds from the Ligase Focused Screening Library
References:
- 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
- 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.
- 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.
- 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.