Abstract
Recent technological advances in flow cytometry provide a versatile platform for high throughput screening of compound libraries coupled with high-content biological testing and drug discovery. The G protein-coupled receptors (GPCRs) constitute the largest class of signaling molecules in the human genome with frequent roles in disease pathogenesis, yet many examples of orphan receptors with unknown ligands remain. The complex biology and potential for drug discovery within this class provide strong incentives for chemical biology approaches seeking to develop small molecule probes to facilitate elucidation of mechanistic pathways and enable specific manipulation of the activity of individual receptors. We have initiated small molecule probe development projects targeting two distinct families of GPCRs: the formylpeptide receptors (FPR/FPRL1) and G protein-coupled estrogen receptor (GPR30). In each case the assay for compound screening involved the development of an appropriate small molecule fluorescent probe, and the flow cytometry platform provided inherently biological rich assays that enhanced the process of identification and optimization of novel antagonists. The contributions of cheminformatics analysis tools, virtual screening, and synthetic chemistry in synergy with the biomolecular screening program have yielded valuable new chemical probes with high binding affinity, selectivity for the targeted receptor, and potent antagonist activity. This review describes the discovery of novel small molecule antagonists of FPR and FPRL1, and GPR30, and the associated characterization process involving secondary assays, cell based and in vivo studies to define the selectivity and activity of the resulting chemical probes.
Keywords: Flow cytometry, fluorescent, GPCR, formylpeptide receptor, inflammation, GPR30, GPER, estrogen, nongenomic, cancer
Current Topics in Medicinal Chemistry
Title: Discovery of Selective Probes and Antagonists for G Protein-Coupled Receptors FPR/FPRL1 and GPR30
Volume: 9 Issue: 13
Author(s): Jeffrey B. Arterburn, Tudor I. Oprea, Eric R. Prossnitz, Bruce S. Edwards and Larry A. Sklar
Affiliation:
Keywords: Flow cytometry, fluorescent, GPCR, formylpeptide receptor, inflammation, GPR30, GPER, estrogen, nongenomic, cancer
Abstract: Recent technological advances in flow cytometry provide a versatile platform for high throughput screening of compound libraries coupled with high-content biological testing and drug discovery. The G protein-coupled receptors (GPCRs) constitute the largest class of signaling molecules in the human genome with frequent roles in disease pathogenesis, yet many examples of orphan receptors with unknown ligands remain. The complex biology and potential for drug discovery within this class provide strong incentives for chemical biology approaches seeking to develop small molecule probes to facilitate elucidation of mechanistic pathways and enable specific manipulation of the activity of individual receptors. We have initiated small molecule probe development projects targeting two distinct families of GPCRs: the formylpeptide receptors (FPR/FPRL1) and G protein-coupled estrogen receptor (GPR30). In each case the assay for compound screening involved the development of an appropriate small molecule fluorescent probe, and the flow cytometry platform provided inherently biological rich assays that enhanced the process of identification and optimization of novel antagonists. The contributions of cheminformatics analysis tools, virtual screening, and synthetic chemistry in synergy with the biomolecular screening program have yielded valuable new chemical probes with high binding affinity, selectivity for the targeted receptor, and potent antagonist activity. This review describes the discovery of novel small molecule antagonists of FPR and FPRL1, and GPR30, and the associated characterization process involving secondary assays, cell based and in vivo studies to define the selectivity and activity of the resulting chemical probes.
Export Options
About this article
Cite this article as:
Arterburn B. Jeffrey, Oprea I. Tudor, Prossnitz R. Eric, Edwards S. Bruce and Sklar A. Larry, Discovery of Selective Probes and Antagonists for G Protein-Coupled Receptors FPR/FPRL1 and GPR30, Current Topics in Medicinal Chemistry 2009; 9 (13) . https://dx.doi.org/10.2174/156802609789753608
DOI https://dx.doi.org/10.2174/156802609789753608 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Drug Targeting to the Brain - A Review
Current Nanoscience Glycoconjugates: Roles in Neural Diseases Caused by Exogenous Pathogens
CNS & Neurological Disorders - Drug Targets Biological Activities of Eco-Friendly Synthesized Hantzsch Adducts
Medicinal Chemistry PI3K Inhibitors for Cancer Therapy: What has been Achieved So Far?
Current Medicinal Chemistry Resveratrol and Ischemic Preconditioning in the Brain
Current Medicinal Chemistry Endothelial Progenitor Cells: Hope Beyond Controversy
Current Cancer Drug Targets Meet Our Editorial Board Member
Recent Patents on Inflammation & Allergy Drug Discovery Actions of the Anti-Angiogenic Compound Angiostatin in an Animal Model of Alzheimer’s Disease
Current Alzheimer Research Resveratrol Protects β Amyloid-Induced Oxidative Damage and Memory Associated Proteins in H19-7 Hippocampal Neuronal Cells
Current Alzheimer Research Recent Development of Anticancer Therapeutics Targeting Akt
Recent Patents on Anti-Cancer Drug Discovery Isolation, Purification and Characterization of a Novel Steroidal Saponin Cholestanol Glucoside from Lasiodiplodia theobromae that Induces Apoptosis in A549 Cells
Anti-Cancer Agents in Medicinal Chemistry Patent Selections:
Current Biomarkers (Discontinued) An Epigenetic Approach to Pancreatic Cancer Treatment: The Prospective Role of Histone Deacetylase Inhibitors
Current Cancer Drug Targets miRNAs in Cancer Prevention and Treatment and as Molecular Targets for Natural Product Anticancer Agents
Current Cancer Drug Targets The Use of Herbal Medicine in Cancer-related Anorexia/ Cachexia Treatment Around the World
Current Pharmaceutical Design Neurokinin-1 Receptor Antagonists in Lung Cancer Therapy
Letters in Drug Design & Discovery Xanthones from Mangosteen Extracts as Natural Chemopreventive Agents: Potential Anticancer Drugs
Current Molecular Medicine Recent Patents in Oncolytic Virotherapy
Recent Patents on Biotechnology Cyclooxygenases in the Central Nervous System: Implications for Treatment of Neurological Disorders
Current Pharmaceutical Design Ceramide and Sphingosine-1-Phosphate in Cell Death Pathways : Relevance to the Pathogenesis of Alzheimer's Disease
Current Alzheimer Research