Editorial [Hot Topic: Screening for Modulators of G Protein-Coupled Receptors (Guest Editor: Guido J.R. Zaman)]

G protein-coupled receptors (GPCRs) represent the largest super family of all receptor types, and account for the major proportion of current drug targets. Many pharmaceutical industries have embarked on high-throughput screening to identify new low molecular weight modulators for GPCRs. Many assay strategies for identification of hits from screening are available. These include assays that address the affinity of compounds for certain receptors, i.e. radioligand binding assays, as well as assays that permit detection of ligands with a certain desired functional effect, such as agonism, antagonism or inverse agonism. The choice of the right assay format strongly impacts on the probability of success of a screening campaign, and sets the direction of the subsequent hit optimization program. Therefore, assays and screening strategies have to be smart. In this mini-hot topic, four papers on assay development and screening strategies for GPCRs have been collected. In: “G protein-coupled receptor assays: To measure affinity or efficacy that is the question,” Christine Williams and Andreas Sewing discuss the practical and theoretical considerations of employing cell-based assays, using examples from the screening portfolio at Pfizer, Sandwich (U.K.). Oren Beske and colleagues from Vitra Bioscience describe a novel technology that allows multiple GPCRs to be assayed simultaneously using the same concentration of compound from the exact same compound source. Their technology may fulfill the need within pharmaceutical industry to understand selectivity at an earlier stage of drug discovery. In addition to the classical coupling and signaling through G proteins, GPCRs demonstrate various other types of behavior [1]. One is receptor internalization. Charlotta Granas and colleagues from BioImage A/S present a case-study on the internalization screening of the chemokine receptor CXCR4 using image-based, high-content screening assay technology. Interesting preliminary data show that compounds can be identified that induce receptor internalization, but with little effect on CXCR4 signaling. Finally, a comprehensive overview of functional cell-based assay approaches for GPCRs is provided by Richard Eglen from DiscoveRx. Recent technological developments, such as new assays to measure inositol phosphate second messengers, are discussed in this review. I would like to thank the authors for their contributions to this mini-hot topic. It has been a pleasure to work with them. I hope you will enjoy reading their articles. REFERENCE [1] Kenakin, T. Annu. Rev. Pharmacol. Toxicol., 2002, 42, 349.