Human GPCR Annotated Library

Description

G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors (GPLR), constitute a large protein family of receptors that detect molecules outside the cell and activate internal signal transduction pathways and, ultimately, cellular responses.
Coupling with G proteins, they are called seven-transmembrane receptors because they pass through the cell membrane seven times

• G protein-coupled receptors (GPCR) are transmembrane proteins
• Physiologically the GPCR function can be modulated by small molecules via

– Direct receptor binders
– Allosteric binders that cause conformational changes within a receptor

• GPCRs are important drug targets and it is believed that 30-50% of marketed drugs target GPCRs for the
broadest spectrum of clinical areas, such as

– CNS disorders, e.g. antidepressants, anxiety, cognitive impairments
– Inflammatory diseases, e.g. rheumatoid arthritis, pain, edema
– Cardiovascular system, e.g. hypertension, atherosclerosis, arterial stiffness
– Metabolic diseases, e.g. diabetes, obesity, appetite

A unique collection of small molecule compounds with annotated activities for GPCR protein targets

❑ Annotated activities : 122 GPCR targets
❑ Express Delivery : 640 compounds
❑ Complete Version : 5800 compounds

Library Composition

Data sources of annotations : ChEMBL 25, PubChem, PubMed, Current Patent Literature (CAS, Integrity)

IDNUMBER – ChemDiv Catalog ID (in some instances the same IDNUMBER might have multiple annotation entries due to multiple data sources or because having activity against multiple similar targets);

UNIPROT – SwissProt and ChEMBL Target accesion ID; Type – character of the measured activity;

Value – Active compounds selection criteria, included only compounds with reported activities < 5 µM;

pubmed_id – PubMed record entry; 

doi, patent_id – journal or patent reference to a publication of original data;

For screening data extracted from PubChem, see column assay_description for entry names PUBCHEM_BIOASSAY

Example of Annotations - an Excel file structure

IDNUMBER	UNIPROT	Target Name	Type	Relation	Value	Units	pubmed_id	doi	patent_id	Target Description	assay_description
1312-0003	P28335	Serotonin 2c (5-HT2c) receptor	EC50	=	51.29	nM			US-20040213816-A1	5-hydroxytryptamine receptor 2C	Agonist activity at 5HT2C receptor VGV isoform (unknown origin) expressed in mouse NIH/3T3 cells by R-SAT assay
8018-3042	P21452	Neurokinin 2 receptor	IC50	=	0.55	nM			US-8470816-B2	Substance-K receptor	Human NK1 Receptor Binding Assay: IM-9 cells.
D349-2536	P21453	Sphingosine 1-phosphate receptor Edg-1	Ki	=	18	nM			US-8889668-B2	Sphingosine 1-phosphate receptor 1	In Vitro Assay: Receptor binding assay: Membranes were prepared from CHO cells expressing S1P1 or S1P3.
0167-0028	P34969	Serotonin 7 (5-HT7) receptor	Ki	=	2	nM	12825922	10.1021/ jm030030n		5-hydroxytryptamine receptor 7	Binding affinity of compound towards rodent 5-hydroxytryptamine 7 receptor
0772-0016	P07550	Beta-2 adrenergic receptor	Kd	=	0.79	nM	19168263	10.1016/ j.ejmech.2008.12.016		Beta-2 adrenergic receptor	Binding affinity to human adrenergic beta2 receptor
8008-6551	P29274	Adenosine A2a receptor	Ki	=	118	nM	16971117	10.1016/ j.bmcl.2006.08.116		Adenosine receptor A2a	Displacement of [3H]CGS21680 from human recombinant adenosine A2A receptor
4111-2066	Q6W5P4	Neuropeptide S receptor	Potency	=	1	nM				Neuropeptide S receptor	PUBCHEM_BIOASSAY: Confirmation Concentration-Response Assay for Antagonists of the Neuropeptide S Receptor: Calcium Signal Transduction SAR for Probe.
5586-4839	O95136	Sphingosine 1-phosphate receptor Edg-5	IC50	=	459	nM				Sphingosine 1-phosphate receptor 2	PUBCHEM_BIOASSAY: Counterscreen for S1P2 Antagonists: Dose Response Cell-Based Screen to Identify Antagonists of CRE-BLA.
C281-0158	P43116	Prostanoid EP2 receptor	Kb	=	22.3	nM	24937185	10.1016/ j.ejmech.2014.05.076		Prostaglandin E2 receptor EP2 subtype	Antagonist activity at EP2 receptor (unknown origin) expressed in rat C6 cells assessed as inhibition of PGE2-induced response
3272-0046	P30559	Oxytocin receptor	Ki	=	67	nM	16302826	10.1021/ jm050645f		Oxytocin receptor	Displacement of [125I]OVTA antagonist from human oxytocin receptor expressed in HEK293-EBNA cells

Publications

1. J. Med. Chem. 2007 50(21):5103-5108. Principal component analysis differentiates the receptor binding profiles of three antipsychotic drug candidates from current antipsychotic drugs. Lange JH Reinders JH Tolboom JT Glennon JC Coolen HK Kruse CG.
2. J. Med. Chem. 2014 57(15):6879-6884. The extracellular entrance provides selectivity to serotonin 5-HT7 receptor antagonists with antidepressant-like behavior in vivo. Medina RA Vázquez-Villa H Gómez-Tamayo JC Benhamú B Martín-Fontecha M de la Fuente T Caltabiano G Hedlund PB Pardo L López-Rodríguez ML.
3. ACS Med. Chem. Lett. 2013 4(10):1005-1010. Discovery of ß2 Adrenergic Receptor Ligands Using Biosensor Fragment Screening of Tagged Wild-Type Receptor. Aristotelous T Ahn S Shukla AK Gawron S Sassano MF Kahsai AW Wingler LM Zhu X Tripathi-Shukla P Huang XP Riley J Besnard J Read KD Roth BL Gilbert IH Hopkins AL Lefkowitz RJ Navratilova I.
4. Nature 2007 450(7169):553-556. An antidepressant that extends lifespan in adult Caenorhabditis elegans. Petrascheck M Ye X Buck LB.
5. MedChemComm 2014 5(5):571-575. Structure-based drug design of chromone antagonists of the adenosine A2A receptor. Andrews SP Mason JS Hurrell E Congreve M
6. ACS Med Chem Lett. 2017 8(6):648-653. Systematic Data Mining Reveals Synergistic H3R/MCHR1 Ligands. Schaller D Hagenow S Alpert G Naß A Schulz R Bermudez M Stark H Wolber G.
7. J. Med. Chem. 2002 45(11):2319-2324. Synthesis receptor potency and selectivity of halogenated diphenylpiperidines as serotonin 5- HT2A ligands for PET or SPECT brain imaging. Fu X Tan PZ Kula NS Baldessarini R Tamagnan G Innis RB Baldwin RM.
8. J. Med. Chem. 2003 46(2):204-206. 3-[(2-Methyl-13-thiazol-4-yl)ethynyl]-pyridine: a potent and highly selective metabotropic glutamate subtype 5 receptor antagonist with anxiolytic activity. Cosford ND Tehrani L Roppe J Schweiger E Smith ND Anderson J Bristow L Brodkin J Jiang X McDonald I Rao S Washburn M Varney MA.
9. J. Med. Chem. 2012 55(4): 1445-1464. Allosteric modulation of seven transmembrane spanning receptors: theory practice and opportunities for central nervous system drug discovery. Melancon BJ Hopkins CR Wood MR Emmitte KA Niswender CM Christopoulos A Conn PJ Lindsley CW.
10. Nat. Chem. Biol. 2005 1(2):98-103. Linking agonist binding to histamine H1 receptor activation. Jongejan A Bruysters M Ballesteros JA Haaksma E Bakker RA Pardo L Leurs R.