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

Abstract

Estimates vary regarding the number of G protein-coupled receptors (GPCRs), the largest family of membrane receptors that are targeted by approved drugs, and the number of such drugs that target GPCRs. We review current knowledge regarding GPCRs as drug targets by integrating data from public databases (ChEMBL, Guide to PHARMACOLOGY, and DrugBank) and from the Broad Institute Drug Repurposing Hub. To account for discrepancies among these sources, we curated a list of GPCRs currently targeted by approved drugs. As of November 2017, 134 GPCRs are targets for drugs approved in the United States or European Union; 128 GPCRs are targets for drugs listed in the Food and Drug Administration Orange Book. We estimate that ∼700 approved drugs target GPCRs, implying that approximately 35% of approved drugs target GPCRs. GPCRs and GPCR-related proteins, i.e., those upstream of or downstream from GPCRs, represent ∼17% of all protein targets for approved drugs, with GPCRs themselves accounting for ∼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. Since ∼100 of the ∼360 human endo-GPCRs (other than olfactory, taste, and visual GPCRs) are orphan receptors (lacking known physiologic agonists), the number of GPCR targets, the number of GPCR-targeted drugs, and perhaps the types of drugs will likely increase, thus further expanding this GPCR repertoire and the many roles of GPCR drugs in therapeutics.

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.

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.

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).

Fig. 4.

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