PMC

Total number of drugs introduced (blue); number of drugs targeting GPCRs as primary mechanism-of-action targets (green); number of non-GPCR drugs that also act on a GPCR at levels higher than 1 μM (yellow), number of non-GPCR drugs predicted to act on GPCRs, with similarity ensemble approach (SEA)-based E-values better than 10⁻⁵⁰ (orange).

A PRESTO-Tango screen of 8,000 drugs and reagents showed opioids as agonists of MRGPRX2. Receptor structure modeling followed by a large-library docking screen revealed a 0.7 μM specific agonist of MRGPRX2 whose stereoisomer is inactive. The molecule, ZINC-3573, is active in a cell-based degranulation assay, whereas it’s stereoisomer is inactive both in signaling assays and in cell culture. The two molecules are openly available as a probe pair from Sigma (http://www.sigmaaldrich.com/catalog/search?interface=All&term=(R)-ZINC-3573&N=0&focus=product&lang=en&region=US). Reprinted from ref. .

(a) Site for the negative allosteric modulator (NAM) sodium in prototypical GPCRs, revealing its conserved location. The small orange and purple dots represent water molecules. (b) The locations of a muscarinic receptor positive allosteric modulator (PAM) and an orthosteric ligand. (c) Smoothened, and the location of various allosteric ligands for which crystal structures have been solved. (d) The elongated pocket defined by these ligands; the arrows illustrate sites for candidate Smoothened ligands.

(a) Shown are typical pathways modulated by G-protein and arrestin (β-arr) biased ligands, which lead to different intracellular signaling pathways and distinct in vivo activities. MAPK, mitogen-activated protein kinase; cAMP, cyclic AMP. (b) A heat map for ligand functional selectivity against the 5HT_2B receptor reveals distinct ligand-specific patterns. Shown are calculated estimates of bias for 5HT_2B agonists at downstream targets. Data are from ref. , and estimates of bias were calculated using the operational model and displayed on a heat map. ERK, extracellular signal-regulated kinase; IP, inositol phosphate; NFAT, nuclear factor of activated T cells.

(a) The investigational new drug oliceridine (TRV130, left) and the lead compound PZM21 (center) do not resemble classical agonists like morphine (right), but both confer analgesia without causing some of the dose-limiting side effects of the classic opioid drugs. (b) The docked pose of PZM21 in the μ-opioid receptor (μOR). Dashed lines represent hydrogen bond interactions and red spheres represent water molecules. (c) G protein (left) biased signaling vs. β-arrestin biased signaling (right) of PZM21. DAMGO is a peptide agonist of the μ opioid receptor, and compound 12 is a precursor to PZM21. Error bars from replicate experiments, as described in ref. . (d) Mouse analgesia of PZM21 vs. vehicle. MPE, maximum possible effect. (e) Respiratory depression conferred by PZM21, morphine, TRV130, and vehicle. Curves for PZM21 are shown in blue, for morphine in red, for TRV130 in green, and for vehicle in black. b–e reprinted from ref. .