Thematic Minireview Series: New Directions in G Protein-coupled Receptor Pharmacology

Abstract

Over the past half-century, The Journal of Biological Chemistry has been the venue for many landmark publications on the topic of G protein-coupled receptors (GPCRs, also known as seven-transmembrane receptors). The GPCR superfamily in humans is composed of about 800 members, and is the target of about one-third of all pharmaceuticals. Most of these drugs target a very small subset of GPCRs, and do so by mimicking or competing with endogenous hormones and neurotransmitters. This thematic minireview series examines some emerging trends in GPCR drug discovery. The first article describes efforts to systematically interrogate the human "GPCR-ome," including more than 150 uncharacterized "orphan" receptors. The second article describes recent efforts to target alternative receptor binding sites with drugs that act as allosteric modulators of orthosteric ligands. The third article describes how the recent expansion of GPCR structures is providing new opportunities for computer-guided drug discovery. Collectively, these three articles provide a roadmap for the most important emerging trends in GPCR pharmacology.A remarkable array of extracellular signals, including photons, single ions, volatile odors, lipids, hormones, neurotransmitters, and proteases, transmit signals via G protein-coupled receptors. Once activated, these receptors engage a G protein heterotrimer, or in some cases accessory proteins such as ␤-arrestins and protein kinases. The G proteins exchange GDP for GTP, and the dissociated ␣ and ␤/␥ subunits then activate various enzymes and ion channels inside the cell. RGS proteins (regulators of G protein signaling) act to counter the effect of GPCRs 2 by accelerating G protein GTPase activity. Much of the literature related to GPCR pharmacology has focused on a relatively small number of hormone and neurotransmitter receptors. Prominent among these are the receptors for epinephrine, histamine, adenosine, acetylcholine, dopamine, serotonin, and opioids. There is a growing realization, however, that GPCRs can also be regulated allosterically. Current efforts to systematically match GPCRs with potential drugs, including both allosteric and orthosteric modulators, are described in the first minireview by Bryan L. Roth and Wesley K. Kroeze (1). The potential of allosteric drugs is detailed in the second minireview written by Patrick R. Gentry, Patrick M. Sexton, and Arthur Christopoulos (2). Additional discovery opportunities, arising from newly available GPCR crystal structures, are described in the third minireview by Ali Jazayeri, Joao M. Dias and Fiona H. Marshall (3).The completion of the human genome sequencing project presented new opportunities, and new challenges, for drug discovery. Prior screening efforts were conducted one receptor at a time, typically with a tailor-made radioligand probe or second messenger assay as a readout. As a consequence, the target space was limited to a very small number of previously characterized receptors. Bryan Roth and his colleagues have been at the forefront of effor...

Recent Advances and Applications of Molecular Docking to G Protein-Coupled Receptors

“…Recently, one can observe a significant improvement in understanding of structure and function of G protein-coupled receptors (GPCRs). This large family of proteins, which includes as many as 800 members [ 1 , 2 ], is responsible for an essential part of signaling in vertebrates and, as such, invariably remains in the spotlight of medicinal chemistry. GPCRs are responsible for receiving signals transmitted by numerous neurotransmitters, like dopamine, serotonin or acetylcholine, as well as for reception of odors, taste or light.…”

Signaling within Allosteric Machines: Signal Transmission Pathways Inside G Protein-Coupled Receptors

“…There are ca. 800 genes encoding GPCRs in human genome, which makes them the largest family of human receptor proteins, and one of the largest protein families in general [ 1 ]. Unsurprisingly, this makes them one of the main drug targets—ca.…”

Using the fragment molecular orbital method to investigate agonist–orexin-2 receptor interactions

“…What is surprising is that these drugs only target approximately 50 of the 800 known GPCRs [4]. Thus there is huge potential in terms of the number of targets for new therapies to be designed against [5]. Further progress of drug discovery for GPCRs is highly dependent on the understanding of structure–function relationships (SAR) and the interactions between the receptor and the small molecule (drug candidate) [4,6–8].…”