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Cross-pharmacology analysis of G protein-coupled receptors.

ABSTRACT: The degree of applicability of chemogenomic approaches to protein families depends on the accuracy and completeness of pharmacological data and the corresponding level of pharmacological similarity observed among their protein members. The recent public domain availability of pharmacological data for thousands of small molecules on 204 G protein-coupled receptors (GPCRs) provides a firm basis for an in-depth cross-pharmacology analysis of this superfamily. The number of protein targets included in the cross-pharmacology profile of the different GPCRs changes significantly upon varying the ligand similarity and binding affinity criteria. However, with the exception of muscarinic receptors, aminergic GPCRs distinguish themselves from the rest of the members in the family by their remarkably high levels of pharmacological similarity among them. Clusters of non-GPCR targets related by cross-pharmacology with particular GPCRs are identified and the implications for unwanted side-effects, as well as for repurposing opportunities, discussed.

SUBMITTER: Brianso F

PROVIDER: S-EPMC3717414 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Cross-pharmacology analysis of G protein-coupled receptors.

Briansó Ferran F Carrascosa Maria C MC Oprea Tudor I TI Mestres Jordi J

Current topics in medicinal chemistry 20110101 15

The degree of applicability of chemogenomic approaches to protein families depends on the accuracy and completeness of pharmacological data and the corresponding level of pharmacological similarity observed among their protein members. The recent public domain availability of pharmacological data for thousands of small molecules on 204 G protein-coupled receptors (GPCRs) provides a firm basis for an in-depth cross-pharmacology analysis of this superfamily. The number of protein targets included ...[more]

PMID: 21851335

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Project description:Heterotrimeric G protein-coupled receptors (GPCRs) comprise the largest receptor family in mammals and are responsible for the regulation of most physiological functions. Besides mediating the sensory modalities of olfaction and vision, GPCRs also transduce signals for three basic taste qualities of sweet, umami (savory taste), and bitter, as well as the flavor sensation kokumi. Taste GPCRs reside in specialised taste receptor cells (TRCs) within taste buds. Type I taste GPCRs (TAS1R) form heterodimeric complexes that function as sweet (TAS1R2/TAS1R3) or umami (TAS1R1/TAS1R3) taste receptors, whereas Type II are monomeric bitter taste receptors or kokumi/calcium-sensing receptors. Sweet, umami and kokumi receptors share structural similarities in containing multiple agonist binding sites with pronounced selectivity while most bitter receptors contain a single binding site that is broadly tuned to a diverse array of bitter ligands in a non-selective manner. Tastant binding to the receptor activates downstream secondary messenger pathways leading to depolarization and increased intracellular calcium in TRCs, that in turn innervate the gustatory cortex in the brain. Despite recent advances in our understanding of the relationship between agonist binding and the conformational changes required for receptor activation, several major challenges and questions remain in taste GPCR biology that are discussed in the present review. In recent years, intensive integrative approaches combining heterologous expression, mutagenesis and homology modeling have together provided insight regarding agonist binding site locations and molecular mechanisms of orthosteric and allosteric modulation. In addition, studies based on transgenic mice, utilizing either global or conditional knock out strategies have provided insights to taste receptor signal transduction mechanisms and their roles in physiology. However, the need for more functional studies in a physiological context is apparent and would be enhanced by a crystallized structure of taste receptors for a more complete picture of their pharmacological mechanisms.

Project description:Asthma is a heterogeneous inflammatory disease of the airways that is associated with airway hyperresponsiveness and airflow limitation. Although asthma was once simply categorized as atopic or nonatopic, emerging analyses over the last few decades have revealed a variety of asthma endotypes that are attributed to numerous pathophysiological mechanisms. The classification of asthma by endotype is primarily routed in different profiles of airway inflammation that contribute to bronchoconstriction. Many asthma therapeutics target G protein-coupled receptors (GPCRs), which either enhance bronchodilation or prevent bronchoconstriction. Short-acting and long-acting β 2-agonists are widely used bronchodilators that signal through the activation of the β 2-adrenergic receptor. Short-acting and long-acting antagonists of muscarinic acetylcholine receptors are used to reduce bronchoconstriction by blocking the action of acetylcholine. Leukotriene antagonists that block the signaling of cysteinyl leukotriene receptor 1 are used as an add-on therapy to reduce bronchoconstriction and inflammation induced by cysteinyl leukotrienes. A number of GPCR-targeting asthma drug candidates are also in different stages of development. Among them, antagonists of prostaglandin D2 receptor 2 have advanced into phase III clinical trials. Others, including antagonists of the adenosine A2B receptor and the histamine H4 receptor, are in early stages of clinical investigation. In the past decade, significant research advancements in pharmacology, cell biology, structural biology, and molecular physiology have greatly deepened our understanding of the therapeutic roles of GPCRs in asthma and drug action on these GPCRs. This review summarizes our current understanding of GPCR signaling and pharmacology in the context of asthma treatment. SIGNIFICANCE STATEMENT: Although current treatment methods for asthma are effective for a majority of asthma patients, there are still a large number of patients with poorly controlled asthma who may experience asthma exacerbations. This review summarizes current asthma treatment methods and our understanding of signaling and pharmacology of G protein-coupled receptors (GPCRs) in asthma therapy, and discusses controversies regarding the use of GPCR drugs and new opportunities in developing GPCR-targeting therapeutics for the treatment of asthma.

Dataset Information

Cross-pharmacology analysis of G protein-coupled receptors.

Publications

Cross-pharmacology analysis of G protein-coupled receptors.

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