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.

Introduction

G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors (GPCRs), also known as 7 transmembrane helical (7TM) receptors, remain a major source of new pharmaceuticals and the focus of extensive research efforts in academia, government and pharma. Recent reviews cover the structural features of the receptors [1], [2], [17] and the chemical aspects of orthosteric [16], [18] and allosteric [88] ligands.

Among the 19 approved drug products with the greatest sales revenues at their peak year in the period up to 2013, 7 are directed toward GPCRs (Table 1) [3]. That is equal to the number of biologic drugs (non-GPCR directed) in the same category of top earners. One of those GPCR drugs, the antithrombotic drug Plavix 1 (Fig. 1) and the highest in revenues during that period, serves as a prodrug that must be activated in the liver [4]. Other GPCR-related drugs in the blockbuster category, such as selective serotonin reuptake inhibitors (SSRIs), increase the synaptic availability of natural neurotransmitters that act at GPCRs. Since 2013, 15 GPCR-related drugs were approved as new chemical entities (NCEs) in 31 months, with exclusions as specified in Table 2. Among these NCEs, naloxegol 12 is a derivative of a known opioid receptor (OR) antagonist that is covalently linked to a short polyethylene glycol (PEG) chain to prevent its intestinal absorption; thus, it selectively blocks opiate receptors in the gut to prevent side effects of systemic opiates [5]. Several of these new drugs treat sleep conditions: suvorexant 10 blocks two subtypes of the orexin receptor, which is a first drug in that category [6]. Approval of a melatonin receptor agonist, tasimelteon 13 followed several other approved drugs acting at the same GPCR [7].

The GPCR field is advancing rapidly, and new paradigms for GPCR drug discovery must be considered in the larger context of drug discovery. Drug discovery for GPCR targets has encountered many of the limitations associated with a changing paradigm for drug discovery in general, and there are many commentaries on why the pharmaceutical pipeline has narrowed [84]. Classical approaches to drug discovery have waning productivity; the linear, stepwise and iterative process through which new compounds progressed is now being modified [8]. Traditionally, the target pathway involved a single mechanism, with one-dimensional activity being measured. The classical approaches have not continued to yield new drugs as in past decades, despite the explosion in the number of new chemical substances accessible to researchers. The resource of greater chemical diversity has not yet led to an increase in the number of approved drugs each year, which is either declining or holding steady. Currently, new approaches to the identification of structural leads and their optimization and new technology for characterizing drug action are aiding GPCR drug discovery [12]. GPCR drug action is much more nuanced than previously recognized, and the uncontrolled variation in formerly neglected or unknown pharmacological parameters can likely lead to a lack of efficacy – or undesirable side effects – in later clinical trials [13]. In addition to directly acting GPCR modulators, many approved drugs influence GPCR action indirectly, for example SSRIs and other inhibitors of the transporter family. This commentary does not cover inhibitors of transport or generation of neurotransmitters, which have been reviewed elsewhere [14]. However, modulation of signaling and regulation pathways directly associated with GPCR activation is within the present scope.