G-Protein-Coupled Receptors in Drug Discovery: Nanosizing Using Cell-Free Technologies and Molecular Biology Approaches

2005 ◽  
Vol 10 (8) ◽  
pp. 765-779 ◽  
Author(s):  
Wayne R. Leifert ◽  
Amanda L. Aloia ◽  
Olgatina Bucco ◽  
Richard V. Glatz ◽  
Edward J. McMurchie
Keyword(s):  
Signal Transduction ◽  
G Protein ◽  
Drug Targets ◽  
G Protein Coupled Receptors ◽  
Orphan Receptors ◽  
Molecular Switching ◽  
Physiological Processes ◽  
Current Cell ◽  
G Protein Coupled ◽  
Signaling Components

Signal transduction by G-protein-coupled receptors (GPCRs) underpins a multitude of physiological processes. Ligand recognition by the receptor leads to activation of a genericmolecular switch involving heterotrimeric G-proteins and guanine nucleotides. Signal transduction has been studied extensively with both cell-based systems and assays comprising isolated signaling components. Interest and commercial investment in GPCRs in areas such as drug targets, orphan receptors, highthroughput screening, biosensors, and so on will focus greater attention on assay development to allow for miniaturization, ultra-high throughput and, eventually, microarray/biochip assay formats. Although cell-based assays are adequate for many GPCRs, it is likely that these formatswill limit the development of higher density GPCRassay platforms mandatory for other applications. Stable, robust, cell-free signaling assemblies comprising receptor and appropriate molecular switching components will form the basis of future GPCR assay platforms adaptable for such applications as microarrays. The authors review current cell-free GPCR assay technologies and molecular biological approaches for construction of novel, functional GPCR assays.

Synthetic GPCRs and signal transduction cascades

2019 ◽  
Vol 3 (5) ◽  
pp. 609-614 ◽  
Author(s):  
Colleen Mulvihill ◽  
Andrew Ellington
Keyword(s):  
Signal Transduction ◽  
Synthetic Biology ◽  
Membrane Proteins ◽  
G Protein ◽  
Drug Targets ◽  
G Protein Coupled Receptors ◽  
Complex Signal ◽  
Diverse Group ◽  
Orthogonal Components ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) are a large and diverse group of membrane proteins that constitute over 30% of FDA approved drug targets. Despite their importance, much remains unknown about GPCR signaling at a system's level. Efforts to engineer receptors with orthogonal components have attempted to provide tools to parse signaling and resultant phenotypes. Recent advances in synthetic biology provide opportunities to engineer receptors at scale and with additional properties that could further inform GPCR biology at a system's level, and enhance the ability to engineer complex signal transduction.

Strategies to identify ligands for orphan G-protein-coupled receptors

2002 ◽  
Vol 30 (4) ◽  
pp. 789-793 ◽  
Author(s):  
G. Milligan
Keyword(s):  
Drug Design ◽  
G Protein ◽  
Small Molecule ◽  
Drug Targets ◽  
G Protein Coupled Receptors ◽  
Orphan Receptors ◽  
Protein Targets ◽  
Small Molecule Drug ◽  
Natural Ligands ◽  
G Protein Coupled

G-protein-coupled receptors are the most tractable class of protein targets for small molecule drug design. Sequencing of the human genome allied to bio-informatic analysis has identified a large number of putative receptors for which the natural ligands remain undefined. A range of currently employed and developing strategies to identify ligands that interact with these orphan receptors and to validate them as drug targets are described and discussed.

scholarly journals The relevance of adhesion G protein-coupled receptors in metabolic functions

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Isabell Kaczmarek ◽  
Tomáš Suchý ◽  
Simone Prömel ◽  
Torsten Schöneberg ◽  
Ines Liebscher ◽  
...  
Keyword(s):  
G Protein ◽  
Drug Targets ◽  
Metabolic Diseases ◽  
Current Knowledge ◽  
G Protein Coupled Receptors ◽  
Specific Expression ◽  
Physiological Functions ◽  
Metabolic Functions ◽  
Central Nervous Systems ◽  
G Protein Coupled

Abstract G protein-coupled receptors (GPCRs) modulate a variety of physiological functions and have been proven to be outstanding drug targets. However, approximately one-third of all non-olfactory GPCRs are still orphans in respect to their signal transduction and physiological functions. Receptors of the class of Adhesion GPCRs (aGPCRs) are among these orphan receptors. They are characterized by unique features in their structure and tissue-specific expression, which yields them interesting candidates for deorphanization and testing as potential therapeutic targets. Capable of G-protein coupling and non-G protein-mediated function, aGPCRs may extend our repertoire of influencing physiological function. Besides their described significance in the immune and central nervous systems, growing evidence indicates a high importance of these receptors in metabolic tissue. RNAseq analyses revealed high expression of several aGPCRs in pancreatic islets, adipose tissue, liver, and intestine but also in neurons governing food intake. In this review, we focus on aGPCRs and their function in regulating metabolic pathways. Based on current knowledge, this receptor class represents high potential for future pharmacological approaches addressing obesity and other metabolic diseases.

Compartmentalization of GPCR signalling controls unique cellular responses

2016 ◽  
Vol 44 (2) ◽  
pp. 562-567 ◽  
Author(s):  
Andrew M. Ellisdon ◽  
Michelle L. Halls
Keyword(s):  
Drug Discovery ◽  
Drug Targets ◽  
Cell Types ◽  
G Protein Coupled Receptors ◽  
Attrition Rates ◽  
Physiological Processes ◽  
Simple Chain ◽  
G Protein Coupled ◽  
Major Drug ◽  
Very High

With >800 members, G protein-coupled receptors (GPCRs) are the largest class of cell-surface signalling proteins, and their activation mediates diverse physiological processes. GPCRs are ubiquitously distributed across all cell types, involved in many diseases and are major drug targets. However, GPCR drug discovery is still characterized by very high attrition rates. New avenues for GPCR drug discovery may be provided by a recent shift away from the traditional view of signal transduction as a simple chain of events initiated from the plasma membrane. It is now apparent that GPCR signalling is restricted to highly organized compartments within the cell, and that GPCRs activate distinct signalling pathways once internalized. A high-resolution understanding of how compartmentalized signalling is controlled will probably provide unique opportunities to selectively and therapeutically target GPCRs.

Identification Methods of G Protein-Coupled Receptors

2011 ◽  
Vol 2 (4) ◽  
pp. 35-52
Author(s):  
Meriem Zekri ◽  
Karima Alem ◽  
Labiba Souici-Meslati
Keyword(s):  
Immune Responses ◽  
G Protein ◽  
Pharmaceutical Research ◽  
G Protein Coupled Receptors ◽  
Machine Learning Algorithms ◽  
Signaling Networks ◽  
Identification Methods ◽  
Physiological Processes ◽  
Cell Signaling Networks ◽  
G Protein Coupled

The G protein-coupled receptors (GPCRs) include one of the largest and most important families of multifunctional proteins known to molecular biology. They play a key role in cell signaling networks that regulate many physiological processes, such as vision, smell, taste, neurotransmission, secretion, immune responses, metabolism, and cell growth. These proteins are thus very important for understanding human physiology and they are involved in several diseases. Therefore, many efforts in pharmaceutical research are to understand their structures and functions, which is not an easy task, because although thousands GPCR sequences are known, many of them remain orphans. To remedy this, many methods have been developed using methods such as statistics, machine learning algorithms, and bio-inspired approaches. In this article, the authors review the approaches used to develop algorithms for classification GPCRs by trying to highlight the strengths and weaknesses of these different approaches and providing a comparison of their performances.

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