Examples

To demonstrate potential of ChemoProfiling MOA for analysis of phenotypic screens we present several examples. The examples are related to independent large scale phenotypic screens covering different therapeutic areas such as Myocardial infarction, Arterial thrombosis and Diabetes. Nevertheless being very different in biological essence or used chemical library, ChemoProfiling analysis reveals similar statistical relationships: in all cases we observe significant statistical links between the ability of a molecule to modulate a particular protein and the chances of a molecule to produce phenotypic transformation.

1. Myocardial infarction

The phenotypic screen "uHTS identification of small molecule modulators of myocardial damage" (PubChem BioAssay 588492) was developed to model "ischemia-reperfusion" stress conditions in cardiomyocytes. The screen was done using H9c2 embryonic myocardium cells (Rattus norvegicus) by adding hydrogen peroxide (to model the oxidative stress of reperfusion) and 2-deoxy-D-glucose (an inhibitor of glycolysis, simulates the metabolic stress of ischemia). In total, 357,249 molecules were tested and 2,272 molecules were classified as active, i.e. efficiently recover H9c2 cells from death after treatment with hydrogen peroxide and 2-deoxy-D-glucose.

ChemoProfiling Output:

2. Arterial thrombosis

The phenotypic screen "MLPCN Platelet Activation-Dense Granule Release" (PubChem BioAssay 1663) aims to identify small molecules that inhibit the activation of platelets by measuring the secretion of ATP-rich dense granules. The inhibitory compounds that can act on diverse mechanisms responsible for platelet activation have been reported (661 active molecules). In total ~300000 molecules have been screened.

ChemoProfiling Output:

3. Diabetes type 1

The phenotypic screen "Luminescence Cell-Based Primary HTS to Identify Inhibitors of Beta Cell Apoptosis" aims to identify small molecules that prevent apoptosis in pancreatic beta cells induced by a combination of cytokines (PubChem BioAssay 435005). Small molecules that increase beta-cell survival in the presence of cytokines could be of potential clinical benefit to early-stage type 1 diabetic patients. The compounds that can act on diverse mechanisms to prevent apoptosis of pancreatic beta cells have been reported (2443 active molecules). In total ~300000 molecules have been screened.

Full Assay Description

ChemoProfiling Output:

4. Hepatic Lipid Droplet Formation

The phenotypic screen "High Throughput Imaging Assay for Hepatic Lipid Droplet Formation " (PubChem BioAssay 1656) was developed to find to identify chemical probes for inhibiting lipid droplet formation in hepatocytes. Identification of such compounds will better our understanding of the biochemical/molecular pathways that lead to the development of fatty liver disease, and may identify lead compounds for consideration for therapeutic development.

In total, 236,559 molecules were tested and 954 molecules were reported as active.

Full Assay Description

ChemoProfiling Output:

  • Valid Active Molecules: 953 molecules were recognized
  • Valid Inactive Molecules: 236,526 molecules were recognized
  • Target/Pathway Enrichment: View Results

5. Lipid Storage Modulators

The phenotypic screen "qHTS Assay for Lipid Storage Modulators in Drosophila S3 Cells " (PubChem BioAssay 2685) was developed to find modulators of lipid storage droplets. In total, 321,194 molecules were tested and 2,061 molecules were reported as active, Full Assay Description

ChemoProfiling Output:

  • Valid Active Molecules: 2,057 molecules were recognized
  • Valid Inactive Molecules: 321,174 molecules were recognized
  • Target/Pathway Enrichment: View Results

6. Aging

The phenotypic screen "Screen for Chemicals that Extend Yeast Lifespan" (PubChem BioAssay 775) was developed to find chemicals that extend yeast lifespan.

In total, 132,796 molecules were tested and 904 molecules were reported as active,

Full Assay Description

ChemoProfiling Output:

  • Valid Active Molecules: 904 molecules were recognized
  • Valid Inactive Molecules: 132,796 molecules were recognized
  • Target/Pathway Enrichment: View Results

7. Colon Cancer

The phenotypic screen "High Throughput Screen to Identify Compounds that Suppress the Growth of Human Colon Tumor Cells Lacking Oncogenic Beta Catenin Expression" (PubChem BioAssay 818) was developed to find for chemicals that that Suppress the Growth of Human Colon Tumor Cells Lacking Oncogenic Beta Catenin Expression .

In total, 138,758 molecules were tested and 2,052 molecules were reported as active,

Full Assay Description

ChemoProfiling Output:

  • Valid Active Molecules: 2,048 molecules were recognized
  • Valid Inactive Molecules: 138,722 molecules were recognized
  • Target/Pathway Enrichment: View Results