GLP1R PAM virtual screen: The data sources

  • GLP1R PAM virtual screen: The data sources
Main data sources come from few GLP1R PubChem screens in the table. 

BioAssay AIDBioAssay NameTested SubstancesActive SubstancesBioAssay Type
624152qHTS of GLP-1 Receptor Agonists: Summary00Summary
624172qHTS of GLP-1 Receptor Agonists375,26823Confirmatory
743262qHTS of GLP-1 Receptor Agonists: Hit Validation1,31123Confirmatory
624148qHTS of GLP-1 Receptor Agonists: LOPAC Validation1,2802Confirmatory
624417qHTS of GLP-1 Receptor Inverse Agonists (Inhibition Mode)408,3526,432Confirmatory
624418qHTS of GLP-1 Receptor Inverse Agonists: Cytotox Screen408,352527Confirmatory

click to go to PubChem screens website

Although Inverse agonists screen has been the main source used to build the ML models, the rest of the data have been employed to characterize different kinds of activity profiles…

Inverse agonism

Inverse agonism with cytotoxicity. 

Inverse agonism with viability enhancement

Agonist activity

Agonist no activity in inverse agonist assay

Agonist & inverse agonist

PAM & agonist

PAM with viability enhancement

PAM, no agonist activity

As inverse agonist assay is based on cAMP measurement on constitutively active GLP1R expressed in HEK293 cells, adenylate cyclase activators, phosphodiesterase inhibitors, and beta 2 adrenergic agonists have been also examined and excluded from model. 

Adenylate cyclase activators

PDE inhibitors

beta2 adrenergic agonists

Additionally, compounds with significant activity at GPCR receptors, Guanine Nucleotide-Binding Protein G(S) Subunit Alpha or promiscuity index above a threshold in ChEMBL are removed from the data set to be employed in the ML model. 
Activity records from GLP1R PAM assays in ChEMBL are also included. 

Tree map withGLP1R assays recorded in ChEMBL, size by number of molecules, color by average activity score based on annotated percentiles.

Reported GLP1R PAMs have been considered too. 

 

compoundtype of activityscoredataInChEmblsourceLiterature
LY3502970agoInLit-pamInChembl7.4YNon-peptide agonists and positive allosteric modulators of glucagon-like peptide-1 receptors: Alternative approaches for treatment of Type 2 diabetes
CATECHINPAM6YNon-peptide agonists and positive allosteric modulators of glucagon-like peptide-1 receptors: Alternative approaches for treatment of Type 2 diabetes
VU0453379PAM6.21YNon-peptide agonists and positive allosteric modulators of glucagon-like peptide-1 receptors: Alternative approaches for treatment of Type 2 diabetes
BETPpamInLit-agoInChembl5.1YNon-peptide agonists and positive allosteric modulators of glucagon-like peptide-1 receptors: Alternative approaches for treatment of Type 2 diabetes
LSN3160440PAM8.05YNon-peptide agonists and positive allosteric modulators of glucagon-like peptide-1 receptors: Alternative approaches for treatment of Type 2 diabetes
V-0219PAM7.15YDiscovery of V-0219: A Small-Molecule Positive Allosteric Modulator of the Glucagon-Like Peptide-1 Receptor toward Oral Treatment for “Diabesity”
PhotoETPPAM6NNon-peptide agonists and positive allosteric modulators of glucagon-like peptide-1 receptors: Alternative approaches for treatment of Type 2 diabetes
N55PAM6NNon-peptide agonists and positive allosteric modulators of glucagon-like peptide-1 receptors: Alternative approaches for treatment of Type 2 diabetes
M_4PAM6NNon-peptide agonists and positive allosteric modulators of glucagon-like peptide-1 receptors: Alternative approaches for treatment of Type 2 diabetes
DA-15864PAM6NNon-peptide agonists and positive allosteric modulators of glucagon-like peptide-1 receptors: Alternative approaches for treatment of Type 2 diabetes
compound19PAM6NNon-peptide agonists and positive allosteric modulators of glucagon-like peptide-1 receptors: Alternative approaches for treatment of Type 2 diabetes
C-1PAM6NNon-peptide agonists and positive allosteric modulators of glucagon-like peptide-1 receptors: Alternative approaches for treatment of Type 2 diabetes
compound20PAM6NNon-peptide agonists and positive allosteric modulators of glucagon-like peptide-1 receptors: Alternative approaches for treatment of Type 2 diabetes
compound2pamInLit-agoInChembl6.52YNon-peptide agonists and positive allosteric modulators of glucagon-like peptide-1 receptors: Alternative approaches for treatment of Type 2 diabetes

Click to open literature references

Reported GLP1R PAM structures

All data sources are combined in a single data frame wmade of 383k molecules with harmonized GLP1R PAM scores, 5.8k classified as actives. 

Activity distribution histogram of filtered potential GLP1R PAMs.