GPCR Focused Screening Library by 2D Similarity

G protein-coupled receptors (GPCRs) are the most intensively studied drug targets, largely due to their substantial involvement in human pathophysiology, their pharmacological tractability and accessibility for small molecule drug discovery.

GPCRs constitute the largest family of proteins targeted by approved drugs. Drugs that currently target GPCRs and GPCR-related proteins are primarily small molecules and peptides.

Life Chemicals has designed a library of potential GPCR modulators based on known structure and activity data for GPCR targeting compounds available publicly. A reference set of molecules with reported GPCR activity data was prepared using ChEMBL database (over 500,000 compounds) and, subsequently, it was narrowed down to meet high activity criteria, such as Inhibition > 50 %, IC50, Ki, EC50 > 1 μM, etc.

A similarity search using 2D molecular fingerprints and Tanimoto similarity metrics (Tanimoto index ≥ 0.85) was then performed against the Life Chemicals HTS Compound Collection. Afterwards, the resulting compound set was filtered with in-house medicinal chemistry filters (PAINS and toxicophore filters, the Rule of Five restrictions).

7,600 drug-like screening compounds with GPCR-privileged scaffolds were selected to facilitate high throughput screening for the discovery of new GPCR ligands. A separate sub-set of 2,200 small-molecule screening compounds is offered based on the known GPCR allosteric modulators (Tanimoto similarity index ≥ 0.8). Each entry is supplied with a link to its Compound Report Card and Bioactivity summary. Some examples of these compounds are shown in Fig. 1.

The following are the examples of GPCR targets against which the Compound Library is focused:

Thyroid-stimulating hormone receptor
Beta-2 adrenergic receptor
Serotonin 2a (5-HT2a) receptor
Opioid receptors; mu & delta
Trace amine-associated receptor 1
Parathyroid hormone receptor
Galanin receptor 3
Orexin receptor 2
Dopamine D3 receptor
Corticotropin-releasing factor receptor 2/Corticotropin-releasing factor-binding protein
G-protein coupled receptor 183
Glucagon-like peptide 1 receptor
Mu opioid receptor
Nociceptin receptor
Adenosine A2a receptor
Cannabinoid CB2 receptor
Omega-3 fatty acid receptor 1
Vasopressin V2 receptor
Type-1 angiotensin II receptor
Proteinase-activated receptor 1
Vasopressin V1a receptor
G-protein coupled bile acid receptor 1
Histamine H3 receptor
Metabotropic glutamate receptor 5
Serotonin 1a (5-HT1a) receptor
Dopamine D2 receptor
Adenosine A1 receptor
Adenosine A2b receptor
Adenosine A3 receptor
Formyl peptide receptor 1
Lipoxin A4 receptor
G-protein coupled receptor 120
Adrenergic receptor beta
Vasoactive intestinal polypeptide receptor 1
Serotonin 2c (5-HT2c) receptor
Serotonin 4 (5-HT4) receptor
Taste receptor type 1 member 3
T1R1/T1R3
T1R2/T1R3
Kappa opioid receptor
Muscarinic acetylcholine receptor M1
Sphingosine 1-phosphate receptor Edg-6
Sphingosine 1-phosphate receptor Edg-5
Orexin receptor 1
Sphingosine 1-phosphate receptor Edg-3
G-protein coupled receptor 55
Sphingosine 1-phosphate receptor Edg-1
Cannabinoid CB1 receptor
G-protein coupled receptor 35
Neuropeptide Y receptor type 2
C-C chemokine receptor type 6
Neuropeptide S receptor
Prokineticin receptor 1
Corticotropin releasing factor receptor 1
Prokineticin receptor 2
Neurokinin 3 receptor
Serotonin 1b (5-HT1b) receptor
5-hydroxytryptamine 1D receptor
Serotonin 6 (5-HT6) receptor
Beta-1 adrenergic receptor
Free fatty acid receptor 1
Melatonin receptor 1A
Melatonin receptor 1B
Dopamine D1 receptor
Serotonin 2b (5-HT2b) receptor
Neurokinin 1 receptor
Histamine H4 receptor
Cholecystokinin B receptor
Adenosine A2 receptor
Serotonin 5a (5-HT5a) receptor
Somatostatin receptor 5
Melatonin receptor
Histamine H1 receptor
Dopamine D4 receptor
Serotonin 2 (5-HT2) receptor
Hydroxycarboxylic acid receptor 2
Alpha-1b adrenergic receptor
Melanin-concentrating hormone receptor 1
Muscarinic acetylcholine receptor M2
Ghrelin receptor
C-C chemokine receptor type 8
Serotonin 7 (5-HT7) receptor
Alpha-1a adrenergic receptor
Serotonin 1d (5-HT1d) receptor
Alpha-1d adrenergic receptor
Adrenergic receptor alpha-2
C-C chemokine receptor type 3
Metabotropic glutamate receptor 2
Cholecystokinin A receptor
Smoothened homolog
G protein-coupled receptor 44
GABA B receptor
Bradykinin B2 receptor
C-C chemokine receptor type 1
Alpha-2a adrenergic receptor
C-C chemokine receptor type 4
Platelet activating factor receptor
Adenosine receptor
Muscarinic acetylcholine receptor M4
Delta opioid receptor
Cysteinyl leukotriene receptor
Angiotensin II receptor
Muscarinic acetylcholine receptor M3
Muscarinic acetylcholine receptor M5
Alpha-2b adrenergic receptor
Free fatty acid receptor 2
Opioid receptor
Melanocortin receptor 4
Neuropeptide Y receptor type 1
Histamine H2 receptor
Cysteinyl leukotriene receptor 1
Beta-3 adrenergic receptor
Neuropeptide Y receptor type 5
Histamine receptor H3
C-C chemokine receptor type 5
Thromboxane A2 receptor
C-C chemokine receptor type 2
Glucose-dependent insulinotropic receptor
Prostanoid EP3 receptor
Serotonin 1f (5-HT1f) receptor
Endothelin receptor ET-A
C-C chemokine receptor type 9
Dopamine receptor
Probable G-protein coupled receptor 139
Interleukin-8 receptor A
Prostanoid EP4 receptor
Serotonin 1 (5-HT1) receptor
Urotensin II receptor
Vasopressin V1b receptor
C5a anaphylatoxin chemotactic receptor
Type-1A angiotensin II receptor
Muscarinic acetylcholine receptor
Dopamine D5 receptor
Follicle stimulating hormone receptor
Serotonin (5-HT) receptor
Oxytocin receptor
G-protein coupled receptor ChemR23
Melanocortin receptor 3
Interleukin-8 receptors, CXCR1/CXCR2
C-X-C chemokine receptor type 3
Angiotensin II type 2 (AT-2) receptor
Somatostatin receptor 2
Bradykinin B1 receptor
Melanocortin receptor 1
Serotonin 1e (5-HT1e) receptor
Somatostatin receptor 3
Adrenergic receptor alpha
Free fatty acid receptor 4
Alpha-2c adrenergic receptor
Prostanoid DP receptor
Calcium sensing receptor
Metabotropic glutamate receptor 6
Olfactory receptor 5K1
Alpha adrenergic receptor 1A and 1B
Melanocortin receptor 5
Glucagon receptor
Probable G-protein coupled receptor 88
Taste receptor type 2 member 14
Metabotropic glutamate receptor 1
C-X-C chemokine receptor type 4
Adrenergic receptor alpha-1

Representative screening compounds from the Life Chemicals Screening Library that possess GPCR modulator activity.

 

Figure 1. Examples of screening compounds from the Life Chemicals Screening Library that possess GPCR modulator activity.

 

References:

  1. Hauser AS, Attwood MM, Rask-Andersen M, Schiöth HB, Gloriam DE. Trends in GPCR drug discovery: new agents, targets, and indications. Nat Rev Drug Discov. 2017; 16(12):829-842.
  2. Sriram K, Insel PA. G Protein-Coupled Receptors as Targets for Approved Drugs: How Many Targets and How Many Drugs? Mol Pharmacol. 2018;93(4):251-258.
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