New paradigms in GPCR drug discovery

Abstract

G protein-coupled receptors (GPCRs) remain a major domain of pharmaceutical discovery. The identification of GPCR lead compounds and their optimization are now structure-based, thanks to advances in X-ray crystallography, molecular modeling, protein engineering and biophysical techniques. In silico screening provides useful hit molecules. New pharmacological approaches to tuning the pleotropic action of GPCRs include: allosteric modulators, biased ligands, GPCR heterodimer-targeted compounds, manipulation of polypharmacology, receptor antibodies and tailoring of drug molecules to fit GPCR pharmacogenomics. Measurements of kinetics and drug efficacy are factors influencing clinical success. With the exception of inhibitors of GPCR kinases, targeting of intracellular GPCR signaling or receptor cycling for therapeutic purposes remains a futuristic concept. New assay approaches are more efficient and multidimensional: cell-based, label-free, fluorescence-based assays, and biosensors. Tailoring GPCR drugs to a patient's genetic background is now being considered. Chemoinformatic tools can predict ADME-tox properties. New imaging technology visualizes drug action in vivo. Thus, there is reason to be optimistic that new technology for GPCR ligand discovery will help reverse the current narrowing of the pharmaceutical pipeline.

Keywords: Drug discovery; GPCR; Inhibitors; Signaling; X-ray crystallography; structure-based design.

Figure 1

The most successful small molecular GPCR ligands (1–7) as of 2013 and the small molecular GPCR ligands that have been approved since 2013 (8–17).

Figure 2

Other structures that are mentioned in the text, including ligands discovered by in silico screening, through receptor docking of diverse molecular libraries and modulators of signaling pathways.

Figure 3

GPCR agonists may be biased for either G protein-dependent or β-arrestin pathways. Other forms of bias are also possible, such as distinguishing between different G proteins [144].

Figure 4

A Gi-biased agonist of the µOR compared to morphine, which also acts through the arrestin pathway [62].

Figure 5

GPCR residence time may be measured using radioligand dissociation [85]. An example of this phenomenon, i.e. a long-acting M₃ muscarinic acetylcholine receptor agonist 46.

Figure 6

Graphical illustration of possible locations and actions of allosteric modulators of GPCRs [88].

Figure 7

X-ray structures of complexes of GPCRs (green ribbon structures, shaded by TM number) and their allosteric modulators (shown in pink) [92,33,97]. PDB accession numbers are: A. M₂ with orthosteric agonist iperoxo and PAM LY2119620 48, 4MQT; B. CRF₁ with NAM CP-376395 49, 4K5Y; C. mGluR1 with NAM FITM 50, 4OR2; D. P2Y₁ with NAM BPTU 51, 4XNV; E. GPR40 with PAM TAK-875 52, 4PHU. Clinical trials of GPR40 agonist fasiglifam (TAK-875) for diabetes were terminated in 2013.

Figure 8

Design of a dual acting drug 55, possibly of use in treating Alzhemier’s disease [117].

Figure 9

GPCR signaling can occur during the endocytic process [118]. The G protein-dependent pathway is, for example, stimulation of cAMP production, and the arrestin pathway includes stimulation of MAPK. Some internalized GPCR proteins are recycled to the surface to restore signaling.

Figure 10

Graphical illustration of possible modes of interaction of monoclonal antibodies with GPCRs. Reprinted with permission from Webb et al. [121].