Phosphatase Screening Library

Phosphatases are enzymes that catalyze the dephosphorylation process. These enzymes replace a phosphate group in a 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.

Life Chemicals has developed a proprietary Phosphatase Screening Library of 2,700 potential phosphatase inhibitors for new HTS drug discovery projects. The Library is designed with a 2D fingerprint similarity search method against reference compounds sets from several databases of bioactive molecules and consists of 2 parts:

Phosphatase Focused Library - Part I

Our similarity search was performed using a reference set of known 12,516 biologically active compounds (Activity (IC50, etc) ≤ 1 µM by PubChem), with their potency being proven in 88 assays (PubChem, DrugBank, ChEBI DBs databases) for the following 59 phosphatase-related targets:

  • Acid phosphatase (Class B, ACP1, Purple)
  • ADP-sugar pyrophosphatase
  • Alkaline phosphatase (tissue-nonspecific isozyme, placental-like, ALPL, intestinal alkaline phosphatase)
  • Aspartate Phosphatase F
  • CTD small phosphatase 1
  • dCTP pyrophosphatase (DCTPP1, ASMTL)
  • Dual Specificity Phosphatase (CDC25 type A/B/C, PTEN, DUSP3)
  • Inositol monophosphatase
  • Inositol-1-phosphatase
  • Lipid-phosphate phosphatase
  • Low molecular weight phosphotyrosine protein phosphatase (ACP1, ets.)
  • PH domain leucine-rich repeat-containing protein phosphatase 1
  • Myosin light chain phosphatase
  • Phos Phosphatase Ahk4
  • Phosphoethanolamine/phosphocholine phosphatase
  • Phosphotyrosine-protein phosphatase PTPB
  • Tyrosine-protein phosphatase non-receptor type (SHP2, PTPN1, PTP1C, PTP2C, PTP4A3, LC-PTP, PTPN1, PTPN1, PTPN2, PTPN11, PTPN22, PTPN6, 70Z-PEP)
  • Protein-tyrosine phosphatase receptor type (PTPRA, PTPRC, PTPRD, PTPRE, PTPRF, PTPRO, PTPRS)
  • Protein-tyrosine phosphatase YopH
  • Pyridoxine 5'-phosphate phosphatase
  • Serine/threonine-protein phosphatase (PP1, PP2A, PP5, PP2C Abi1, PP2C HAB1, PP2C PH domain, PP1 Regulatory Subunit 71)
  • Undecaprenyl pyrophosphate phosphatase

The Life Chemicals HTS Compound 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 of 85 %. Ro5 compliance is indicated; reactive, toxic or PAINS compounds are excluded from the Library. As a result, over 2,100 drug-like screening compounds were identified and added to the Library.

Phosphatase Focused Library - Part II (Similarity search against ChEMBL DB)

The compound reference set of 3,395 unique reported phosphatase inhibitors was prepared based on ChEMBL database entriesin accordance with the accepted maximum activity value (IC50 < 1 uM). Subsequently, a similarity search, using 2D fingerprints, generated with the Unity module of Sybyl-X, was applied to the reference set (Tanimoto similarity cut-off of 85 %).

This enabled us to identify and add to the Library almost 600 close analogs of known phosphatase binders, targeting the following phosphatases:

  • Alkaline phosphatase tissue-nonspecific isozyme
  • Alkaline phosphatase placental-like
  • Dual specificity phosphatase Cdc25A
  • Dual specificity phosphatase Cdc25B
  • Dual specificity protein phosphatase 3
  • Hematopoietic cell protein-tyrosine phosphatase 70Z-PEP
  • Intestinal alkaline phosphatase
  • Low molecular weight phosphotyrosine protein phosphatase
  • PH domain leucine-rich repeat-containing protein phosphatase 1
  • Phosphoethanolamine/phosphocholine phosphatase
  • Phosphotyrosine-protein phosphatase PTPB
  • Protein-tyrosine phosphatase 1B
  • Protein-tyrosine phosphatase 2C
  • Protein-tyrosine phosphatase LC-PTP
  • Receptor-type tyrosine-protein phosphatase O
  • Receptor-type tyrosine-protein phosphatase S

 Example of representative analogues of the Phosphatase Screening Library selected based on the reference compound set

Figure 1. Example of representative analogues of the Phosphatase Screening Library selected based on the reference compound set.

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