scholarly journals G Protein-coupled Receptors: One of the Most Important Drug Discovery Targets

2018 ◽  
Vol 25 (2) ◽  
pp. 27-35
Author(s):  
Yusra Saleh Andijani
Keyword(s):  
Drug Discovery ◽  
G Protein ◽  
Inflammatory Diseases ◽  
G Protein Coupled Receptors ◽  
Allosteric Modulators ◽  
Biased Agonism ◽  
The Central Nervous System ◽  
Almost All ◽  
Complex Signaling ◽  
G Protein Coupled

G protein-coupled receptors are considered the most widely investigated drug discovery targets. They are the largest family of receptors with almost 800 genes in humans. Different types of ligands can activate these receptors, such as catecholamines, nucleotides, lipids, and gut microbiota, where some ligands could be bitopic. Nevertheless, some receptors have internal ligands bound to them. Activated G protein-coupled receptors have complex signaling pathways that are involved in almost all bodily functions. Furthermore, they constitute a large percentage of Food and Drug Administration marketed drugs and global share of drugs, in addition to a great proportion of drugs currently in clinical trials targeting these receptors. The approved G protein-coupled receptors targeted drugs and potential drugs are involved in the management of many diseases including cancer, inflammatory diseases, diabetes mellitus, hypertension, obesity, pain, and diseases of the central nervous system. Only 10% of G protein-coupled receptors are targeted. Different pharmacological approaches have been considered in drug discovery of these receptors including polypharmacology, allosteric modulators, biased agonism, tethered agonism, and pharmacogenomics. Advances in the technologies are promising to help in the discovery of new targets. The review's aim is to discuss the importance of G protein-coupled receptors as drug discovery targets.

scholarly journals Advances in the molecular understanding of G protein-coupled receptors and their future therapeutic opportunities

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Daniel N. Obot ◽  
Godswill J. Udom ◽  
Anwanabasi E. Udoh ◽  
Nkechi J. Onyeukwu ◽  
Ayobami J. Olusola ◽  
...  
Keyword(s):  
Drug Discovery ◽  
G Protein ◽  
Drug Targets ◽  
Inflammatory Diseases ◽  
G Protein Coupled Receptors ◽  
Main Body ◽  
Target Class ◽  
Proper Diagnosis ◽  
Approved Drugs ◽  
G Protein Coupled

Abstract Background Understanding the mechanisms, activated and inhibited pathways as well as other molecular targets involved in existing and emerging disease conditions provides useful insights into their proper diagnosis and treatment and aids drug discovery, development and production. G protein-coupled receptors (GPCRs) are one of the most important classes of targets for small-molecule drug discovery. Of all drug targets, GPCRs are the most studied, undoubtedly because of their pharmacological tractability and role in the pathophysiology as well as the pathogenesis of human diseases. Main body of the abstract GPCRs are regarded as the largest target class of the “druggable genome” representing approximately 19% of the currently available drug targets. They have long played a prominent role in drug discovery, such that as of this writing, 481 drugs (about 34% of all FDA-approved drugs) act on GPCRs. More than 320 therapeutic agents are currently under clinical trials, of which a significant percentage targets novel GPCRs. GPCRs are implicated in a wide variety of diseases including CNS disorders, inflammatory diseases such as rheumatoid arthritis and Crohn’s disease, as well as metabolic disease and cancer. The non-olfactory human GPCRs yet to be clinically explored or tried are endowed with perhaps a huge untapped potential drug discovery especially in the field of immunology and genetics. Short conclusion This review discusses the recent advances in the molecular pharmacology and future opportunities for targeting GPCRs with a view to drug development.

scholarly journals Natural Compounds as Guides for the Discovery of Drugs Targeting G-Protein-Coupled Receptors

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 5060
Author(s):  
Joan Serrano-Marín ◽  
Irene Reyes-Resina ◽  
Eva Martínez-Pinilla ◽  
Gemma Navarro ◽  
Rafael Franco
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
G Protein ◽  
Natural Compounds ◽  
G Protein Coupled Receptors ◽  
Taste Receptors ◽  
Allosteric Modulators ◽  
Chemical Structures ◽  
Therapeutic Drugs ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs), which constitute the most populous family of the human proteome, are the target of 35–45% of approved therapeutic drugs. This review focuses on natural products (excluding peptides) that target GPCRs. Natural compounds identified so far as agonists, antagonists or allosteric modulators of GPCRs have been found in all groups of existing living beings according to Whittaker’s Five Kingdom Classification, i.e., bacteria (monera), fungi, protoctists, plants and animals. Terpenoids, alkaloids and flavonoids are the most common chemical structures that target GPCRs whose endogenous ligands range from lipids to epinephrine, from molecules that activate taste receptors to molecules that activate smell receptors. Virtually all of the compounds whose formula is displayed in this review are pharmacophores with potential for drug discovery; furthermore, they are expected to help expand the number of GPCRs that can be considered as therapeutic targets.

Novel Insights into Biased Agonism at G Protein-Coupled Receptors and their Potential for Drug Design

2013 ◽  
Vol 19 (28) ◽  
pp. 5156-5166 ◽  
Author(s):  
Maria Marti-Solano ◽  
Ramon Guixa-Gonzalez ◽  
Ferran Sanz ◽  
Manuel Pastor ◽  
Jana Selent
Keyword(s):  
Drug Design ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Biased Agonism ◽  
G Protein Coupled

scholarly journals Applications of molecular replacement to G protein-coupled receptors

2013 ◽  
Vol 69 (11) ◽  
pp. 2287-2292 ◽  
Author(s):  
Andrew C. Kruse ◽  
Aashish Manglik ◽  
Brian K. Kobilka ◽  
William I. Weis
Keyword(s):  
G Protein ◽  
Structural Biology ◽  
Structural Information ◽  
G Protein Coupled Receptors ◽  
Integral Membrane Proteins ◽  
Molecular Replacement ◽  
Gpcr Activation ◽  
Health And Disease ◽  
Almost All ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) are a large class of integral membrane proteins involved in regulating virtually every aspect of human physiology. Despite their profound importance in human health and disease, structural information regarding GPCRs has been extremely limited until recently. With the advent of a variety of new biochemical and crystallographic techniques, the structural biology of GPCRs has advanced rapidly, offering key molecular insights into GPCR activation and signal transduction. To date, almost all GPCR structures have been solved using molecular-replacement techniques. Here, the unique aspects of molecular replacement as applied to individual GPCRs and to signaling complexes of these important proteins are discussed.

scholarly journals Integrating High-Content Analysis into a Multiplexed Screening Approach to Identify and Characterize GPCR Agonists

2014 ◽  
Vol 19 (7) ◽  
pp. 1079-1089 ◽  
Author(s):  
Yingjie Zhu ◽  
John Watson ◽  
Mengjie Chen ◽  
Ding Ren Shen ◽  
Melissa Yarde ◽  
...  
Keyword(s):  
Drug Discovery ◽  
G Protein Coupled Receptors ◽  
High Content Imaging ◽  
Biased Agonism ◽  
Receptor Oligomerization ◽  
Sphingosine 1 Phosphate ◽  
High Content Analysis ◽  
Screening Assays ◽  
Hit Identification ◽  
G Protein Coupled

G protein–coupled receptors (GPCRs) are one of the most popular and proven target classes for therapeutic intervention. The increased appreciation for allosteric modulation, receptor oligomerization, and biased agonism has led to the development of new assay platforms that seek to capitalize on these aspects of GPCR biology. High-content screening is particularly well suited for GPCR drug discovery given the ability to image and quantify changes in multiple cellular parameters, to resolve subcellular structures, and to monitor events within a physiologically relevant environment. Focusing on the sphingosine-1-phosphate (S1P1) receptor, we evaluated the utility of high-content approaches in hit identification efforts by developing and applying assays to monitor β-arrestin translocation, GPCR internalization, and GPCR recycling kinetics. Using these approaches in combination with more traditional GPCR screening assays, we identified compounds whose unique pharmacological profiles would have gone unnoticed if using a single platform. In addition, we identified a compound that induces an atypical pattern of β-arrestin translocation and GPCR recycling kinetics. Our results highlight the value of high-content imaging in GPCR drug discovery efforts and emphasize the value of a multiassay approach to study pharmacological properties of compounds of interest.

scholarly journals Prospects for use of peptides and their derivatives, structurally corresponding to the G protein-coupled receptors, in medicine

2015 ◽  
Vol 61 (1) ◽  
pp. 19-29 ◽  
Author(s):  
A.O. Shpakov ◽  
E.A. Shpakova
Keyword(s):  
G Protein ◽  
Intracellular Signaling ◽  
High Efficiency ◽  
Clinical Medicine ◽  
Inflammatory Diseases ◽  
G Protein Coupled Receptors ◽  
Signaling Cascades ◽  
G Protein Coupled

The regulation of signaling pathways involved in the control of many physiological functions is carried out via the heterotrimeric G protein-coupled receptors (GPCR). The search of effective and selective regulators of GPCR and intracellular signaling cascades coupled with them is one of the important problems of modern fundamental and clinical medicine. Recently data suggest that synthetic peptides and their derivatives, structurally corresponding to the intracellular and transmembrane regions of GPCR, can interact with high efficiency and selectivity with homologous receptors and influence, thus, the functional activity of intracellular signaling cascades and fundamental cellular processes controlled by them. GPCR-peptides are active in both in vitro and in vivo. They regulate hematopoiesis, angiogenesis and cell proliferation, inhibit tumor growth and metastasis, and prevent the inflammatory diseases and septic shock. These data show greatest prospects in the development of the new generations of drugs based on GPCR-derived peptides, capable of regulating the important functions of the organism.

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