Supplemental material to this article can be found at: http://molpharm.aspetjournals.org/content/suppl/2018/01/03/mol.117.111062.DC1 1521-0111/93/4/251–258$35.00 https://doi.org/10.1124/mol.117.111062 MOLECULAR PHARMACOLOGY Mol Pharmacol 93:251–258, April 2018 Copyright ª 2018 by The American Society for Pharmacology and Experimental Therapeutics MINIREVIEW—AXELROD SYMPOSIUM 2017 G Protein-Coupled Receptors as Targets for Approved Drugs: How Many Targets and How Many Drugs? s Krishna Sriram and Paul A. Insel Departments of Pharmacology (K.S., P.A.I.) and Medicine (P.A.I.), University of California San Diego, La Jolla, California Downloaded from Received November 8, 2017; accepted December 21, 2017 ABSTRACT Estimates vary regarding the number of G protein-coupled drugs target GPCRs. GPCRs and GPCR-related proteins, i.e., receptors (GPCRs), the largest family of membrane receptors those upstream of or downstream from GPCRs, represent molpharm.aspetjournals.org that are targeted by approved drugs, and the number of such ∼17% of all protein targets for approved drugs, with GPCRs drugs that target GPCRs. We review current knowledge themselves accounting for ∼12%. As such, GPCRs consti- regarding GPCRs as drug targets by integrating data from tute the largest family of proteins targeted by approved public databases (ChEMBL, Guide to PHARMACOLOGY, and drugs. Drugs that currently target GPCRs and GPCR- DrugBank) and from the Broad Institute Drug Repurposing related proteins are primarily small molecules and peptides. Hub. To account for discrepancies among these sources, we Since ∼100 of the ∼360 human endo-GPCRs (other than curated a list of GPCRs currently targeted by approved drugs. olfactory, taste, and visual GPCRs) are orphan receptors As of November 2017, 134 GPCRs are targets for drugs (lacking known physiologic agonists), the number of GPCR approved in the United States or European Union; 128 GPCRs targets, the number of GPCR-targeted drugs, and perhaps are targets for drugs listed in the Food and Drug Administra- the types of drugs will likely increase, thus further expanding at ASPET Journals on September 27, 2021 tion Orange Book. We estimate that ∼700 approved drugs this GPCR repertoire and the many roles of GPCR drugs in target GPCRs, implying that approximately 35% of approved therapeutics. Introduction clarify this ambiguity, we reviewed information from three majorpublicdatabases(seeMaterials and Methods). We report Based on their canonical structure, G protein-coupled recep- here the results of this analysis regarding the identity and tors (GPCRs), which are sometimes termed heptahelical or number of GPCR targets and drugs that target those GPCRs, as 7-transmembrane receptors, are the largest family of mem- well as GPCR-related proteins upstream (e.g., ligands) and brane receptors in humans and numerous other species. In downstream (e.g., phosphodiesterases [PDEs] that degrade addition, GPCRs are considered the largest family of targets for cAMP). In addition, we provide information about the types of approved drugs (Allen and Roth, 2011; Rask-Andersen et al., chemical entities that are GPCR-directed therapeutics and 2014; Santos et al., 2017). Numerous factors contribute to the identify inconsistencies among the databases regarding GPCR wide utility of GPCR-targeted drugs, including their drugg- targets and drugs directed at those targets. ability, interaction with numerous types of chemical entities, and expression in the plasma membrane, which facilitates Materials and Methods molecular interactions in the extracellular milieu. Scientific We assessed information regarding approved drugs, drug targets, articles, grant applications, and lectures that describe findings and if available ligand-target interactions from three online data- related to GPCRs often note the therapeutic utility of GPCRs bases: ChEMBL (Bento et al., 2014), DrugBank (Wishart et al., 2007), but differ widely in estimates of their contribution as targets for and the International Union of Basic and Clinical Pharmacology/BPS approved drugs, which generally range from ∼20% to .50%. To (British Pharmacological Society) Guide to PHARMACOLOGY (GtoPdb) (Southan et al., 2016; Alexander et al., 2017). We consoli- This work was supported by the American Society of Pharmacology and dated data from each source into tables that relate the drugs approved Experimental Therapeutics (ASPET) David Lehr Award, and by grants from the for use in humans to their targets. We obtained a list of all annotated National Institutes of Health (R21AG52914, R21AG053568) and the Department human GPCRs (excluding olfactory and vision receptors) from GtoPdb of Defense (W81XWH-14-1-0372), and a contract with Bristol-Myers Squibb. (Alexander et al., 2017); the genes/proteins on this list were then https://doi.org/10.1124/mol.117.111062. s This article has supplemental material available at molpharm. queried from different sources to identify GPCRs that are drug aspetjournals.org. targets. Approved drugs were cross-checked against those listed by ABBREVIATIONS: BPS, British Pharmacological Society; EMA, European Medicines Agency; FDA, Food and Drug Administration; GPCR, G protein-coupled receptor; GtoPdb, Guide to PHARMACOLOGY; HRH1, histamine H1 receptor; PDE, phosphodiesterase. 251 252 Sriram and Insel the Food and Drug Administration (FDA) (fda.gov) and European Numerous approved drugs are physiological agonists for Medicines Agency (EMA) (ema.europa.eu/ema/). As an additional GPCRs (for example, epinephrine [at multiple adrenergic source, we used data from the Broad Institute Drug Repurposing receptors] and numerous peptide hormones). Entries in bold Hub (Corsello et al., 2017), which employed high-throughput screen- in Table 1 indicate GPCRs considered primary targets for the ing to characterize drug-target interactions of approved drugs, natural listed drug, based on affinity and/or functional response (in the products, and nutraceuticals along with other entities. majority of cases, both). Entries not in bold indicate GPCRs Our analysis yielded a list of currently druggable GPCRs and the drugs that target them. Because of possible database errors in targeted by approved drugs but for which such an interaction downloadable material, as well as ambiguity of ligand-target interac- is not likely a primary aspect of the intended therapeutic use tions in certain sources, we manually curated each druggable GPCR to of such drugs. Such GPCR-ligand interactions may contribute verify pharmacological interaction of the approved drugs. The primary to side effects. In a number of cases, data are ambiguous sources used for crosschecking the data were the aforementioned regarding precisely which receptors are responsible for medi- databases, plus the Drug Gene Interaction Database (dgidb.org; Cotto ating the therapeutic efficacy of GPCR-targeted drugs. In such et al, 2017) and GeneCards (genecards.org; Rebhan et al., 1998), along cases, if pharmacological data implicate a strong GPCR-drug with primary sources cited within these databases. affinity, we list GPCR-drug pairs in bold. An example is the The resulting list of GPCRs targeted by approved drugs (Table 1) melanocortin receptor family (MC1R–MC5R), which may includes an example of an approved drug that targets each GPCR. mediate a number of therapeutic effects of corticotropin/ Certain GPCRs (for example, histamine H1) are the targets for multiple Downloaded from drugs. Supplemental Table 2 lists all such GPCR-targeted drugs. In adrenocorticotropin (ACTH; Gong, 2014). Similarly, the pre- some cases, we considered families of GPCRs as targets for the same cise importance of each of the somatostatin receptors as drugs (e.g., multiple P2Y receptors are targets for suramin and multiple targets for pasireotide and lanreotide is incompletely un- S1P receptors as targets for fingolimod). For such examples, we list the derstood (e.g., Feelders et al., 2012). In total, we thus list GPCRs and approved drugs with the caveat that some of the drug- 98 GPCRs that are thought to mediate therapeutic effects of GPCR interactions are not well defined. In certain cases (e.g., suramin), approved drugs, with an additional 36 GPCRs that interact the approval status of a drug is unclear; we provide details for such with approved drugs and may contribute to therapeutic effects molpharm.aspetjournals.org drugs in Table 1 and the accompanying legend. or side effects. We excluded multiple GPCRs as primary We thus assembled an integrated list of approved drugs that target targets for molecules with affinity for multiple members GPCRs by combining data from the previously noted databases within one or more GPCR families. As examples, caffeine (ChEMBL, GtoPdb, and DrugBank) and the Broad Drug Repurposing Hub. Due to difficulties in cross-referencing information among the and theophylline bind multiple adenosine receptors including databases (since common identifiers such as Chemical Abstracts ADORA2B, but we do not consider that receptor to be a Service numbers are not provided for drugs listed by all sources), we primary target for any approved drugs. Our rationale is generated lists of GPCR-related drugs using drug names. We consid- similar for suramin, which binds multiple P2Y receptors. ered drugs with multiple derivatives (such as different salts) as Different databases/sources identify differing numbers and duplicates in counting GPCR-related drugs and evaluating over- identities of GPCRs that are targets of approved drugs. at ASPET Journals on September