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G protein-coupled receptors (GPCRs) - Articles and news items


Development of biosensor assays for fragment screening of wild type GPCRs

Webinars / 14 October 2015 /

In this webinar, we discuss SPR fragment screening of wild type GPCRs enabled by sensitive biosensors and optimised membrane protein assays…

The evolving field of PCR

The evolving field of PCR : which method will you choose?

Issue 6 2014 / 23 December 2014 / Natalia Meani and Manuela Vecchi

Recognised as one of the major scientific breakthroughs of the 20th century, polymerase chain reaction (PCR) is a quick and simple method to create, in a test tube, millions of copies of a given DNA segment from a complex mixture of genetic material. This method has greatly stimulated biochemical, molecular biology and genetic research and, given its ability to amplify DNA from limited amounts of biologic samples, including fossils, opened the way for new applications in medicine, genetics, biotechnology, forensics and paleobiology…

Domain Therapeutics logo

Domain Therapeutics appoints Professor Michel Bouvier as chairman of the Scientific Advisory Board

Industry news / 22 September 2014 / Domain Therapeutics

The world-renowned GPCR specialist will assemble a team of experts in drug discovery and development to guide Domain’s programs…

Figure 1: Principle of protein fragment complementation. Two interacting proteins are fused to N and C terminal fragments of a fluorescent or luminescent reporter protein (generic depicted in yellow). Upon interaction, the activity of the reporter is reconstituted and can be read out as fluorescence upon excitation (2) or as luminescence upon substrate addition (3)

Cell-based assays for protein-protein interactions

Issue 5 2013, Screening / 22 October 2013 / Mark Wade, Center for Genomic Science of IIT@SEMM

Protein-protein interactions (PPI) form the backbone of all cellular signalling networks, and aberrant PPI contribute to the pathology of several diseases. Thus, strategies to identify PPI modulators are expected to be therapeutically beneficial. However, there are very few examples of clinically approved PPI modulators, reflecting the difficulties of identifying effective compounds for this target class. This perspective reviews the challenges associated with targeting PPI, and summarises the major strategies used to detect and disrupt PPI, with a particular focus on cell-based assays for PPI.

Cell based label-free assays in GPCR drug discovery

GPCRs: Cell based label-free assays in GPCR drug discovery

Drug Targets, Issue 4 2013 / 20 August 2013 / Niklas Larsson, Linda Sundström, Erik Ryberg and Lovisa Frostne (AstraZeneca)

G protein-coupled receptors are one of the major classes of therapeutic targets for a broad range of diseases. The most commonly used assays in GPCR drug discovery measure production of second messengers such as cAMP or IP3 that are the result of activation of individual signalling pathways. Such specific assays are unable to provide a holistic view of the cell response after GPCR activation. This is now changing as label-free technologies and assays on whole cells have been developed that are unbiased towards the specific downstream pathways and capture the integrated cell response. In this mini-review, we focus on the application of one of these technologies, namely resonant waveguide grating (RWG) for measurements of dynamic mass redistribution (DMR) in intact cells upon GPCR activation. Since the technology is sensitive and non-invasive, it is applicable to most cell types, including primary cells with native receptor expression levels. We discuss how DMR assays have become an important component of GPCR drug discovery screening cascades and may have the potential to improve the ability to predict if compounds will be efficacious in vivo.

Drug Targets Supplement 2012

Drug Targets: In-depth focus 2012

Drug Targets, Issue 6 2012, Supplements / 11 December 2012 / Patricia McDonald / Emmanuel Sturchler / Dayue Darrel Duan

GPCR allosteric modulation: new opportunities and challenges for drug discovery.
Chloride channels and cardiac arrhythmia: novel therapeutic targets?

Figure 1: Classification Scheme of GPCRs. R (Rhodopsin-like), S (Secretin-like), G (Glutamate-like), Others (Adhesion, Frizzled, Taste type-2, unclassified)

G protein coupled receptors – exploiting flexible conformations

Drug Targets, Issue 4 2012 / 3 September 2012 / Kathryn L. Chapman, Imperial Drug Discovery Centre, Imperial College London and John B.C. Findlay & Gemma K. Kinsella, Department of Biology, National University of Ireland Maynooth

G-protein coupled receptors (GPCRs) are a diverse super-family of proteins located within the plasma membrane of eukaryotic cells which have a common architecture consisting of seven-transmembrane (7-TM) segments, connected by extracellular (ECL) and intracellular (ICL) loops. They differ from other 7-TM proteins in their ability to activate guanine-nucleotide binding proteins or β-arrestin and so initiate a signalling cascade. They have a wide range of physiological roles and provide many successful drug targets, playing a role in disorders including allergies, cardiovascular dysfunction, depression, obesity, cancer, pain, diabetes and a variety of central nervous system conditions. This review will give a general overview of GPCRs and how their structures and activities can be used in drug discovery…

Figure 1

GPCR screening and drug discovery: Challenges and latest trends

Drug Targets, Issue 2 2012 / 26 April 2012 / Sofia M.A. Martins, João R.C. Trabuco, Gabriel A. Monteiro and Duarte Miguel Prazeres, Institute for Biotechnology and Bioengineering, Instituto Superior Técnico, Technical University of Lisbon

G-protein coupled receptors (GPCRs) are one of the most popular drug targets today. Almost one third of the approved drugs currently available rely on some kind of interaction with these receptors. The annual revenues are around USD 30 billion (109) and the fact that one quarter of the top US selling drugs are GPCR-related puts this drug target under the drug discovery spotlight. Also, GPCRs are one of the largest families in the human genome, with nearly 1,000 sequences identified as likely to be GPCRs. Among these, around 100 sequences have been confirmed as receptors, but have no known ligand or function. These so-called orphan receptors harbour the highest drug discovery potential. Still, even amongst the non-orphan receptors, only a handful are actually targeted by drugs…

FIGURE 1 Schematic overview of a typical homology modelling procedure that is used to build threedimensional coordinates for a protein of unknown structure

Status and challenges in structure-based drug discovery for G protein-coupled receptors

Drug Targets, Issue 6 2011 / 13 December 2011 / Henri Xhaard, Head of Computational Drug Discovery Group, Centre for Drug Research, University of Helsinki

The central location of G protein-coupled receptors (GPCRs) at the interface between the interior and exterior of cells, as well as their key role in signalling events, make GPCRs a prominent class of pharmaceutical targets. To date, approximately 40 per cent of known drugs are thought to act on GPCRs either directly or indirectly. GPCRs are for the most part inaccessible to structural determination due to difficulties to express, purify and crystallise them; however, progress of structure determination has led to seven new structures in the last decade. This number is still insufficient to conduct structure-based drug discovery on all available targets. Computational modelling is therefore a very useful surrogate and in this paper I discuss the reliability of atomistic three-dimensional models that are obtained through molecular modelling in light of the GPCRdock 2008 and 2010 competitions organised by the Scripps Institute. G protein coupled receptors (GPCRs) are key proteins involved in signalling and as such are prominent drug targets. Ligands that bind to GPCRs include small aminergic neuro – transmitters or hormones such as noradrenaline and adrenaline, dopamine, histamine, small peptides, nucleic acids, lipids or even opsins that contain light-reactive retinal chromophores. Altogether, in the human genome project, about 390 non-olfactory GPCRs have been identified; of which about 100 are orphan proteins without an identified ligand or cellular function…

FIGURE 1 Structures of active and inactive conformations of the β2 adrenoceptor Structures of the β2 adrenoceptor (light grey) in an inactive conformation with the antagonist carazolol bound (left33), and in an active conformation in complex with Gs (dark grey) and the agonist BI-167107 bound (right41). In both cases, the ligand is represented by black spheres to show the location of the orthosteric binding site within the membrane-spanning region of the protein. T4 lysozyme (black) is inserted in the third intracellular loop between helices 5 and 6 in the inactive structure (bottom left), and fused in the extracellular N-terminus for the active structure (top right), to remove flexibility and to provide polar surfaces for crystallisation. The nanobody (black, bottom right) served to stabilise the open conformation of Gs and also provided crystallisation contacts

Lead discovery for targeting G protein-coupled receptors

Drug Targets, Issue 5 2011 / 19 October 2011 / Sandra Siehler and Sandra W. Cowan-Jacob, Novartis Institutes for BioMedical Research

G protein-coupled receptors (GPCRs) control a plethora of key physiological functions in every cell of an organism. GPCRs are therefore involved in many diseases, since altered ligand or receptor levels and genetic or epigenetic modifications can lead to GPCR dysfunction and hence a pathophysiological phenotype. About one third of currently marketed drugs target GPCRs. The human genome contains 720-800 predicted GPCRs, and about half of them respond to olfactory/sensory signals, whereas the others are known or predicted to be activated by endogenous ligands and many of these represent potential drug targets. Seventy seven per cent of these non-sensory GPCRs belong to the class A (rhodopsin-like) family, whereas 14 per cent represent class B (secretin-like) GPCRs, less than one per cent belong to the class C (metabotropic receptor-like) or the atypical frizzled-/smoothened receptor class, and the remaining 25 per cent are orphan receptors…


Whitepaper: The importance of being profiled: Improving drug candidate safety and efficacy using cross-target profiling

Whitepapers / 11 July 2011 / Merck Millipore

Profiling of putative lead compounds against a representative panel of important enzymes, receptors, ion channels and transporters is an excellent way to establish a preliminary view of potential issues that might later hamper development. An early idea of which off-target activities must be minimized can save valuable time and money during the preclinical lead optimization phase if pivotal questions are asked beyond the usual profiling at hERG. The best data for critical evaluation of activity at GPCRs and ion channels is obtained using functional assays, since binding assays cannot detect all interactions and do not provide information on whether the interaction is that of an agonist, antagonist, or allosteric modulator. This overview discusses the benefits of in vitro assays, specific decision points where profiling can be of immediate benefit, and highlights relevant profiling services offered by Merck Millipore.


AstraZeneca and Heptares collaborate to investigate important GPCR drug targets

Industry news, News / 31 May 2011 / AstraZeneca

AstraZeneca & Heptares entered a four-year collaboration focused on the potential discovery & development of new medicines…


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