GPCR 2D Similarity Focused Library

G protein-coupled receptors (GPCRs) are the most intensively studied drug targets, mostly due to their substantial involvement in human pathophysiology and their pharmacological tractability. As of November 2017, there were 134 GPCRs targets for drugs approved in the United States or European Union; and there were 128 GPCRs targets for drugs listed in the FDA orange book. We estimate that about 700 approved drugs target GPCRs, implying that approximately 35 % of approved drugs target those receptors. GPCRs and GPCR-related proteins, i.e. those upstream or downstream of GPCRs, represent around 17 % of all protein targets for approved drugs, with GPCRs themselves accounting for about 12 %. As such, 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.

We designed the library of potential GPCR activity modulators that is based on known structure and activity data for GPCR targeting compounds available publicly. Compounds from the Life Chemicals Stock Screening Collection have initially been processed with medicinal chemistry filters that include PAINS and toxicophore filters and the Rule of Five restrictions. Thereafter, 2D similarity search was performed, based on a reference set of compounds derived from ChEMBL (500,000 compounds) with the use of 2D molecular fingerprints and Tanimoto similarity metrics (T ≥ 0.85). Before the search, the reference set has been narrowed down to meet a high activity criteria such as Inhibition > 50 %, IC50, Ki, EC50 > 1 uM, etc. 

The resulting Life Chemicals GPCR 2D Similarity Focused Library comprises 7,639 compounds. A separate compound sub-set (2,254 compounds) is offered as based on the known allosteric modulators of GPCR (T ≥ 0.80). Each compound is supplied with a link to its Compound Report Card and Bioactivity summary.

The Library comprises drug-like compounds selected by computational chemistry and virtual screening techniques and is intended for screening in GPCR-related drug discovery projects. Some examples of these compounds are shown below:

The following are the examples of GPCR targets against which the Library compounds are 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
  • Taste receptor type 2 member 14
  • Metabotropic glutamate receptor 1
  • C-X-C chemokine receptor type 4
  • Adrenergic receptor alpha-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

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.