It is generally known that G protein-coupled receptors (GPCRs) are a large family of cell surface signaling receptors that are associated with many physiological functions, including tumor growth and metastasis [1-3]. Up to date, 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 biggest family of proteins targeted by approved drugs. In fact, 40 % of marketed drugs (mostly, small molecules and peptides) target GPCRs and GPCR-related proteins. Meanwhile, there are no approved drugs or candidates in clinical development targeting 60 % of non-olfactory GPCRs, which makes them intriguing drug targets [4].
Our cheminformatics team has designed a dedicated Screening Library of a total of 62,500 drug-like screening compounds that are potential GPCR modulators, representing close analogs of the reported GPCR targeting compounds.
The compound selection can be customized based on your requirements, cherry picking is available.
Please, contact us at orders@lifechemicals.com for any additional information and price quotations.
Figure1. GP-first mechanism of GP activation [5].
Compound selection
A reference set of molecules with reported GPCR activity data was prepared using the ChEMBL database (over 500,000 compounds) and, subsequently, narrowed down to meet high activity criteria, such as Inhibition > 50 %, IC50, Ki, EC50 > 1 μM, etc.
The similarity search using 2D molecular fingerprints and Tanimoto similarity metrics (Tanimoto index ≥ 0.85) was then performed against the Life Chemicals HTS Compound Collection. The resulting compound set was filtered with in-house medicinal chemistry filters (PAINS and toxicophore filters, the Rule of Five restrictions).
As a result, around 60,300 drug-like screening compounds with GPCR-privileged scaffolds were selected to facilitate high throughput screening for the discovery of new GPCR ligands. Each entry is supplied with a link to its Compound Report Card and Bioactivity Summary.
Additionally, a dedicated Screening Set of 2,200 small-molecule compounds was designed based on the known GPCR allosteric modulators (Tanimoto similarity index ≥ 0.8).
Presented below are the examples of GPCR targets against which this Screening Compound Library is focused:
- Adenosine receptor (A1,A2,A3)
- Adrenergic receptor alpha (1a,1b,1d, 2a,2c), beta (1,2,3)
- Angiotensin II receptor (AT-1,AT-1a, AT-2)
- Apelin receptor
- Bradykinin receptor (B1,B2)
- Calcitonin-gene-related peptide receptor, CALCRL/RAMP1
- Calcium sensing receptor
- Cannabinoid receptor (CB1,CB2)
- C-C chemokine receptor (1-9)
- Cholecystokinin B receptor
- Corticotropin releasing factor receptor (1,2)
- C-X3-C chemokine receptor (1,3,4,6,7)
- Cysteinyl leukotriene receptor
- D(2) dopamine receptor/ Metabotropic glutamate receptor 5
- Delta opioid receptor
- Dopamine receptor (D1,D2,D3,D4)
- Endothelin receptor (ET-A, ET-B)
- Formyl peptide receptor 1
- Free fatty acid receptor (1,2)
- GABA receptor (A,B)
- Galanin receptor 3
- Ghrelin receptor
- Glucagon receptor
- Glucagon-like peptide 1 receptor
- Glucose-dependent insulinotropic receptor
- GPCR
- G-protein coupled bile acid receptor 1
- G-protein coupled estrogen receptor 1
- G-protein coupled receptor (44,120,183,35,4,55,6,84,ChemR23)
- Histamine receptor (H1,H2,H3,H4)
- HM74 nicotinic acid GPCR
- Human herpesvirus 5 chemokine receptor
- Hydroxycarboxylic acid receptor 2
- Interleukin-8 receptor (A,B, CXCR1/CXCR2)
- Kappa opioid receptor
- Leukotriene B4 receptor
- Lipoxin A4 receptor
- Mas-related G-protein coupled receptor member X4
- Melanin-concentrating hormone receptor 1
- Melanocortin receptor (1,4,5)
- Melatonin receptor (1A,1B)
- Metabotropic glutamate receptor (1-8)
- Metastin receptor
- Motilin receptor
- Mu opioid receptor
- Muscarinic acetylcholine receptor (M1-M5)
- N-arachidonyl glycine receptor
- Neurokinin receptor (1,3)
- Neuromedin-U receptor 1
- Neuropeptide S receptor
- Neuropeptide Y receptor (1,2,5)
- Neuropeptides B/W receptor type 1
- Nociceptin receptor
- Opioid growth factor receptor-like protein 1
- Opioid receptor (delta & kappa,mu & kappa)
- Orexin receptor (1,2)
- P2Y purinoceptor 14
- Parathyroid hormone receptor
- Platelet activating factor receptor
- Probable G-protein coupled receptor (139,174,27,52,88)
- Prokineticin receptor (1,2)
- Prostanoid DP receptor
- Prostanoid EP3 receptor
- Prostanoid EP4 receptor
- Proteinase-activated receptor (1,2)
- Pyroglutamylated RFamide peptide receptor
- Relaxin receptor 1
- Relaxin-3 receptor 1
- Serotonin receptor ((5-HT), 1a (5-HT1a), 1b (5-HT1b), 1d (5-HT1d), 2 (5-HT2), 2a (5-HT2a), 2b (5-HT2b), 2c (5-HT2c), 3 (5-HT3), 3a (5-HT3a), 4 (5-HT4), 5a (5-HT5a), 6 (5-HT6), 7 (5-HT7)
- Sigma opioid receptor
- Smoothened homolog
- Somatostatin receptor (3,5)
- Sphingosine 1-phosphate receptor (Edg-1,Edg-3,Edg-5,Edg-6,Edg-8)
- T1R1/T1R3
- T1R2/T1R3
- Taste receptor type 2 member 14
- Thromboxane A2 receptor
- Thyroid stimulating hormone receptor
- Trace amine-associated receptor 1
- Uracil nucleotide/cysteinyl leukotriene receptor
- Urotensin II receptor
- Vasoactive intestinal polypeptide receptor 1
- Vasopressin receptor ( V1a, V1b, V2)
Representative screening molecules from the GPCR Focused Library
References:
- 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.
- 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.
- Chaudhary PK, Kim S. An Insight into GPCR and G-Proteins as Cancer Drivers. Cells. 2021;10(12):3288. Published 2021 Nov 24. doi:10.3390/cells10123288
- Laeremans T, Sands ZA, Claes P, et al. Accelerating GPCR Drug Discovery With Conformation-Stabilizing VHHs. Front Mol Biosci. 2022;9:863099. Published 2022 May 23. doi:10.3389/fmolb.2022.863099
- Mafi A, Kim SK, Goddard WA 3rd. The mechanism for ligand activation of the GPCR-G protein complex. Proc Natl Acad Sci U S A. 2022;119(18):e2110085119. doi:10.1073/pnas.2110085119
- https://www.ncbi.nlm.nih.gov/pmc/articles/instance/9170043/bin/pnas.2110085119fig01.jpg