Phosphatases are enzymes that catalyze dephosphorylation process. These enzymes replace a phosphate group on the substrate with a hydroxyl group from activation water. The action of phosphatases is directly opposite to that of phosphorylases and kinases. They play a significant role in signal transduction pathways and control a vast variety of cellular processes, including metabolism, gene transcription and translation, cell-cycle progression, cytoskeletal rearrangement, protein-protein interactions, protein stability, cell movement and apoptosis.
Applying similarity search method against reference compounds sets from ChEMBL and PubChem databases, Life Chemicals has designed two libraries of small molecule compounds with predicted activity towards phosphatase targets.
Phosphatase Targeted Library I (Similarity search against ChEMBL DB)
Using 2D fingerprints, generated with Unity module of Sybyl-X, a Tanimoto similarity cut-off of 85 % was applied for screening of a reference set of known active compounds taken from ChEMBL database.
All compounds in the reference set were chosen in accordance with accepted maximum activity value (IC50 < 1000 nM). In total, 830 compounds were included into the reference set for subsequent similarity search. As a result over 700 similarcompounds were extracted and added to the targeted library.
The list of targeted phosphatases:
- Dual specificity phosphatase Cdc25A
- Dual specificity protein phosphatase 3
- Protein-tyrosine phosphatase 1B
- Protein-tyrosine phosphatase LC-PTP
- Protein-tyrosine phosphatase 2C
- Receptor-type tyrosine-protein beta
- Hematopoietic cell protein-tyrosine 70Z-PEP
- Protein-tyrosine phosphatase G1
Phosphatase Targeted Library II (Similarity search against PubChem DB)
We started with a reference set of known 12,516 biologically active compounds with proven potency in 88 phosphatase assays for the following 18 targets:
- PPP5C (protein phosphatase 5, catalytic subunit)
- PPP1CA (protein phosphatase 1, catalytic subunit, alpha isoform)
- Impa1 (Inositol (myo)-1(or 4)-monophosphatase 1)
- PHOSPHO1 (phosphatase, orphan 1)
- PTPN7 (protein tyrosine phosphatase, non-receptor type 7)
- PTPN22 (protein tyrosine phosphatase, non-receptor type 22 (lymphoid))
- DUSP3 (dual specificity phosphatase 3)
- Dusp6 (dual specificity phosphatase 6)
- ALPL (alkaline phosphatase, liver/bone/kidney)
- ALPPL2 (alkaline phosphatase, placental-like 2)
- RNGTT (RNA guanylyltransferase and 5'-phosphatase)
- PTPRJ (protein tyrosine phosphatase, receptor type, J)
- DUSP1 (dual specificity phosphatase 1)
- CDC25B (cell division cycle 25 homolog B (S. pombe)
- PTPN14 (protein tyrosine phosphatase, non-receptor type 14)
- PTPRR (protein tyrosine phosphatase, receptor type, R)
- PTPRK (protein tyrosine phosphatase, receptor type, K)
- PTPN5 (protein tyrosine phosphatase, non-receptor type 5 (striatum-enriched)
The Life Chemicals Stock Collection was searched for small molecules similar to the compounds included in the reference database using MDL public keys and the Tanimoto similarity cut-off 90 %. As a result of this effort, 1,146 compounds were identified and added to the targeted library.