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Research ArticleMinireview—Axelrod Symposium 2017

G Protein-Coupled Receptors as Targets for Approved Drugs: How Many Targets and How Many Drugs?

Krishna Sriram and Paul A. Insel
Molecular Pharmacology April 2018, 93 (4) 251-258; DOI: https://doi.org/10.1124/mol.117.111062
Krishna Sriram
Departments of Pharmacology (K.S., P.A.I.) and Medicine (P.A.I.), University of California San Diego, La Jolla, California
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Paul A. Insel
Departments of Pharmacology (K.S., P.A.I.) and Medicine (P.A.I.), University of California San Diego, La Jolla, California
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  • Fig. 1.
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    Fig. 1.

    The number of GPCRs targeted by approved drugs. (A) The number of GPCRs targeted by approved drugs, based on annotations of GPCR-drug interactions from each of several sources. Also included is the number of commonly listed (consensus) GPCRs and GPCRs curated in our analysis. The number of druggable GPCRs uniquely listed in each source is as follows: GtoPdb, 6; ChEMBL, 3; DrugBank, 0; and Broad Institute Drug Repurposing Hub, 24. (B) Putative primary Gα protein linkage, based on classification of GPCR signaling by GtoPdb, of the 134 curated GPCRs targeted by approved drugs. Individual GPCRs may couple to multiple G-proteins. (C and D) Venn diagrams of the GtoPdb’s list of GPCR drug targets and that of ChEMBL and DrugBank.

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    Fig. 2.

    The estimated proportion of genes from different gene families that are targets for approved drugs. GPCRs comprise the single largest such group. VGICs: voltage-gated ion channels; LGICs: ligand-gated ion channels.

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    Fig. 3.

    The number of GPCR-targeted drugs. (A) The number of approved drugs identified in GtoPdb, CHEMB, DrugBank, and the Broad repurposing hub with the consensus among the four sources and each entry combined from the four sources. (B) The percentage of approved drugs that target GPCRs in each database. (C) Venn diagram showing the relationship between identities of GPCR-related drugs listed in the GtoPdb and ChEMBL databases. (D) The types of molecules that target GPCRs, based on annotations from GtoPdb (Alexander et al., 2017).

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    Fig. 4.

    The 15 GPCRs with the most approved drugs and the number of such drugs listed in ChEMBL, DrugBank, and GtoPdb.

Tables

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    TABLE 1

    One hundred thirty-four GPCRs have FDA-approved drugs

    Exceptions are those marked as follows: *, EMA approved; 1, approved in the United Kingdom by the The Medicines and Healthcare products Regulatory Agency (MHRA); 2, suramin is not listed in the FDA’s Orange Book, but is distributed by the Centers for Disease Control and is listed as an essential medicine by the World Health Organization; and #, GABBR1 and 2 combine to form a single active signaling complex that is activated by baclofen. Entries in bold in indicate GPCRs considered primary targets for the listed drug based on affinity and/or functional response (in the majority of cases, both). Entries not in bold indicate GPCRs targeted by approved drugs but for which such an interaction is not likely a primary aspect of the intended therapeutic use of such drugs.

    Gene NameExample of an Approved Drug
    ACKR3Plerixafor
    ADGRG3Beclometasone dipropionate
    ADORA1Adenosine
    ADORA2ARegadenoson
    ADORA2BTheophylline
    ADORA3Nicardipine
    ADRA1AOxymetazoline
    ADRA1BPrazosin
    ADRA1DPrazosin
    ADRA2AApraclonidine
    ADRA2BDexmedetomidine
    ADRA2CDexmedetomidine
    ADRB1Acebutolol
    ADRB2Pindolol
    ADRB3Mirabegron
    AGTR1Candesartan
    AVPR1AVasopressin
    AVPR1BVasopressin
    AVPR2Vasopressin
    BDKRB1Icatibant
    BDKRB2Icatibant
    CALCRCalcitonin
    CASREtelcalcetide
    CCKARCeruletide
    CCKBRPentagastrin
    CCR4Plerixafor
    CCR5Maraviroc
    CHRM1Biperiden
    CHRM2Propantheline
    CHRM3Umeclidinium
    CHRM4Acetylcholine
    CHRM5Acetylcholine
    CNR1Nabilone
    CNR2Nabilone
    CRHR1Corticorelin ovine triflutate
    CXCR4Plerixafor
    CYSLTR1Zafirlukast
    CYSLTR2Zafirlukast
    DRD1Dopamine
    DRD2Dopamine
    DRD3Dopamine
    DRD4Dopamine
    DRD5Dopamine
    EDNRAAmbrisentan
    EDNRBBosentan
    F2RVorapaxar
    FFAR1Rosiglitazone
    FPR1Cyclosporine
    FSHRHuman follicle stimulating hormone
    GABBR1 #Baclofen
    GABBR2 #Baclofen
    GCGRGlucagon
    GHRHRSermorelin
    GLP1RLixisenatide
    GLP2RTeduglutide
    GNRHRAbarelix
    GPBAR1Deoxycholic acid
    GPER1Estradiol
    GPR143Levodopa
    GPR18Dronabinol
    GPR35Bumetanide
    GPR55Dronabinol
    GPR68Lorazepam
    HCAR1Sodium oxybate
    HCAR2Acipimox 1
    HCAR3Nicotinic acid
    HCRTR1Suvorexant
    HCRTR2Suvorexant
    HRH1Cetirizine
    HRH2Betazole
    HRH3Pitolisant *
    HRH4Clozapine
    HTR1AVilazodone
    HTR1BFrovatriptan
    HTR1DFrovatriptan
    HTR1EAsenapine
    HTR1FEletriptan
    HTR2AAsenapine
    HTR2BMethysergide
    HTR2CMethysergide
    HTR4Cisapride
    HTR5AErgotamine
    HTR6Amoxapine
    HTR7Lurasidone
    LHCGRChoriogonadotropin alfa
    MC1RCorticotropin
    MC2RCorticotropin
    MC3RCorticotropin
    MC4RCorticotropin
    MC5RCorticotropin
    MLNRErythromycin
    MRGPRX1Chloroquine
    MTNR1ARamelteon
    MTNR1BTasimelteon
    NPY4RNiclosamide
    NTSR2Levocabastine
    OPRD1Naltrexone
    OPRK1Anileridine
    OPRM1Alfentanil
    OXTROxytocin
    P2RY1Suramin 2
    P2RY11Suramin 2
    P2RY12Cangrelor
    P2RY13Cangrelor
    P2RY2Suramin 2
    P2RY6Suramin 2
    PTGDRTreprostinil
    PTGDR2Indomethacin
    PTGER1Prostaglandin E1
    PTGER2Prostaglandin E2
    PTGER3Misoprostol
    PTGER4Treprostinil
    PTGFRLatanoprost
    PTGIREpoprostenol
    PTH1RTeriparatide
    PTH2RTeriparatide
    S1PR1Fingolimod
    S1PR2Fingolimod
    S1PR3Fingolimod
    S1PR4Fingolimod
    S1PR5Fingolimod
    SCTRSecretin
    SMOSonidegib
    SSTR1Pasireotide
    SSTR2Lanreotide
    SSTR3Pasireotide
    SSTR4Octreotide
    SSTR5Lanreotide
    SUCNR1Sodium succinate
    TAAR1Dexamfetamine
    TACR1Aprepitant
    TBXA2RIloprost
    TRHRProtirelin
    TSHRThyrotropin
    • View popup
    TABLE 2

    GPCR-related proteins/genes that are targets for approved drugs

    Examples of Proteins/Genes That Are Drug TargetsExamples of Drugs That Target These Proteins/Genes
    Protein/gene category: enzymes involved in agonist synthesis
     Prostaglandin I2 synthaseEpoprostenol
     Angiotensin I converting enzymesLisinopril
     Dopamine beta-hydroxylaseHydralazine
     Coagulation factors (e.g., factor 10)Rivaroxaban
    Protein/gene category: enzymes involved in agonist degradation
     Monoamine oxidases A and BPhenelzine
     Catechol O-methyltransferaseEntacapone
     AcetylcholinesteraseNeostigmine
     Adenosine deaminasePentostatin
     Dipeptidyl peptidase-4Sitagliptin
    Protein/gene category: transporters of GPCR agonists
     Serotonin transportersCitalopram
     Dopamine transporters (SLC6A3)Modafinil
     ATP transporters (SLC25A4)Clodronic acid
    Protein/gene category: GPCR ligands
     C-C motif chemokine ligand 2Mimosine
     Coagulation factor II, thrombinArgatroban
    Protein/gene category: regulators of second messenger signaling
     PDEs
     PDE1A-CVinpocetine
     PDE4A-DRoflumilast
     Rho Kinases (ROCK1-2)Fasudil

Additional Files

  • Figures
  • Tables
  • Data Supplement

    • Supplemental Table 1 -

      The GPCRs identified as targeted by approved drugs from each source, plus a list of all human GPCRs annotated by IUPHAR, which does not include olfactory receptors

    • Supplemental Table 2  -

      A list of all drugs, between the different sources indicated, which target GPCRs

    • Supplemental Table 3 -

      Lists of all drugs, in each of the three major databases (CHEMBL, IUPHAR and DRUGBANK) indicated as targeting each GPCR

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Molecular Pharmacology: 93 (4)
Molecular Pharmacology
Vol. 93, Issue 4
1 Apr 2018
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Research ArticleMinireview—Axelrod Symposium 2017

How Many G Protein-Coupled Receptors are Drug Targets?

Krishna Sriram and Paul A. Insel
Molecular Pharmacology April 1, 2018, 93 (4) 251-258; DOI: https://doi.org/10.1124/mol.117.111062

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Research ArticleMinireview—Axelrod Symposium 2017

How Many G Protein-Coupled Receptors are Drug Targets?

Krishna Sriram and Paul A. Insel
Molecular Pharmacology April 1, 2018, 93 (4) 251-258; DOI: https://doi.org/10.1124/mol.117.111062
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