Editorial [Hot Topic: G Protein-Coupled Receptor Drug Targets (Executive Editors: P.M. Sexton and A. Christopoulos)]

G protein-coupled receptors (GPCRs) represent the largest known single gene family in the human genome. This superfamily of cell-surface proteins also constitutes the major target for approximately half the medicines on the market today. This issue of Current Pharmaceutical Design focuses on different aspects of the biology and the study of these receptors, with a broad emphasis on how these studies are influencing the modern drug discovery process. In her article, Evi Kostenis [2] presents an overview of functional assay systems for GPCRs that take advantage of the best-known signal transduction system associated with these receptors, namely, that of the G proteins themselves. The ability to translate ligand dependent and independent modulation of GPCRs into a measurable functional response in a manner that is as portable across GPCR systems as possible remains an important priority, and challenge, to GPCR-based drug discovery. The article describes how the manipulation of G protein alpha subunits, in particular, has been used to address this issue with respect to high throughput screening of GPCRs. Ethan Burstein and colleagues [3] focus on the emergence of chemical genomics, which combines genomic information, combinatorial chemistry and functional high throughput screening to accelerate drug discovery. In particular, the utility of functional assay platforms that allow a common screening approach against the widest possible array of genomic targets are discussed. The role of GPCR constitutive activity, intracellular signalling promiscuity, and G protein independent signaling are discussed within the context of general strategies for creating homogeneous assay platforms. Jen Estall and Daniel Drucker [4] focus on a specific subset of GPCRs, those targeted by glucagon and glucagonlike peptides, and discuss the potential of these receptors as drug targets. These receptors play essential roles in energy intake, absorption and disposal, and are currently hot targets with respect to diabetes, the regulation of food intake and related metabolic conditions both in the central nervous system and the periphery. The current state of knowledge with respect to selective agonists and antagonists, as well as specific aspects of the regulation of this system, are discussed. In their article, Spiro Pavlopoulos and colleagues [5] focus on another specific GPCR family that has also emerged as a very promising therapeutic target in recent years, namely the cannabinoid CB1 and CB2 receptors. Although there has been anectodal evidence for medicinal properties of cannabis and cannabis-related compounds for centuries, it is only in the modern molecular era that significant attempts have been made to delineate the biology of the receptors for these compounds and to design compounds that maintain therapeutic efficacy while minimizing and/or eliminating unwanted psychoactive effects. The discovery of endogenous cannabinoid compounds has greatly facilitated this process, and the article focuses on essential pharmacophoric elements that can be used to lead to selective signalling at cannabinoid receptors. Lei Shi and Jonathan Javitch [6] turn their attention to the area of informatics as applied to the study of GPCRs. Specifically, they highlight the key role for informatic approaches utilizing sequence information, mutagenesis data and the vast published literature to facilitate studies of GPCRs in the current climate characterized by a dearth of atomic resolution models. General approaches for integrating the vast amounts of information already available in databases and the literature, and the application to structure-funciton studies of GPCRs, are presented. Bryan Roth and Wesley Kroeze [7] draw attention to the wealth of therapeutic targets potentially available in the "receptorome", i.e., that portion of the human genome that encodes all receptors. By using a series of illuminating case studies, they demonstrate how massively parallel screening of the receptorome is a powerful drug discovery platform that can validate drug targets and yield novel information not only on mechanisms of drug action, but also on previously poorly understood mechanisms underlying drug side-effects. In addition, an overview of useful GPCR-related databases is also provided. Finally, Ignacio Torrecilla and Andrew Tobin [8] highlight the importance of delineating mechanisms that regulate GPCRs beyond the acute effects mediated by drugs that either activate or inhibit these receptors. In particular, their article focuses on the dynamic mechanisms that underlie covalent modifications of these receptors mediated by the processes of phosphorylation, palmitoylation and ubiquitination; it is envisaged that these pathways can provide alternative targets to the GPCRs themselves in the drug discovery process.We are extremely grateful to all our contributors for their efforts and patience during the preparation of this issue, and believe that it will serve as a timely overview of much of the state of play in GPCR-based drug discovery. References [1] Werry TD, Christopoulos A, Sexton PM. Mechanisms of ERK1/2 Regulation by Seven-Transmembrane- Domain Receptors. Curr Pham Design 2006; 12(14): 1683-1702. [2] Kostenis E. G Proteins in Drug Screening: From Analysis of Receptor-G Protein Specificity to Manipulation of GPCR-Mediated Signalling Pathways. Curr Pham Design 2006; 12(14): 1703-1715. [3] Burstein ES, Piu F, Ma J-N, Weissman JT, Currier EA, Nash NR, Weiner DM, Spalding TA, Schiffer HH, Tredici ALD, Brann MR. Integrative Functional Assays, Chemical Genomics and High Throughput Screening: Harnessing Signal Transduction Pathways to a Common HTS Readout. Curr Pham Design 2006; 12(14): 1717-1729. [4] Estall JL, Drucker DJ. Glucagon and Glucagon-Like Peptide Receptors as Drug Targets. Curr Pham Design 2006; 12(14): 1731-1750. [5] Pavlopoulos S, Thakur GA, Nikas SP, Makriyannis A. Cannabinoid Receptors as Therapeutic Targets. Curr Pham Design 2006; 12(14): 1751-1769. [6] Shi L, Javitch JA. A Role for Information Collection, Management, and Integration in Structure-Function Studies of G-Protein Coupled Receptors. Curr Pham Design 2006; 12(14): 1771-1783. [7] Roth BL, Kroeze WK. Screening the Receptorome Yields Validated Molecular Targets for Drug Discovery. Curr Pham Design 2006; 12(14): 1785-1795. [8] Torrecilla I, Tobin AB. Co-Ordinated Covalent Modification of G-Protein Coupled Receptors. Curr Pham Design 2006; 12(14): 1797-1808.