Abstract
Peroxisome Proliferator Activated Receptors (PPARs) are a family of three related nuclear receptors first cloned in 1990. Their involvement in glucidic and lipidic homeostasis quickly made them an attractive target for the treatment of metabolic syndrome, the most prevalent mortality factor in developed countries. They therefore attracted much synthetical efforts, more particularly PPARγ. Supported by a large number of crystallographic studies, data derived from these compounds lead to a fairly clear view of the agonist binding mode into the Ligand Binding Domain (LBD). Nearly all the compounds conform to a three-module structure, with a binder group involved in a series of hydrogen bonds in front of the ligand-dependent Activation Function (AF2), a linker mostly arranged around a phenoxyethyl and an effector end occupying the large cavity of the binding site. Following the marketing of the glitazones and the observation of the hepatotoxicity of troglitazone, variations in the binder led to the glitazars, and then pharmacomodulations have been undertaken on the two other modules, leading to a large family of highly related chemical structures. Some compounds, while still adhering to the three-module structure, diverge from the mainstream, such as the phthalates. Curiously, these plasticizers were known to elicit biological effects that led to the discovery of PPARs but were not actively studied as PPARs agonists. As the biological effects of PPARs became clearer, new compounds were also found to exert at least a part of their actions by the activation of PPARγ.
Keywords: PPARγ, agonist, binding mode, crystallography, docking
Current Medicinal Chemistry
Title: Structural Insight into PPARγ Ligands Binding
Volume: 16 Issue: 14
Author(s): A. Farce, N. Renault and P. Chavatte
Affiliation:
Keywords: PPARγ, agonist, binding mode, crystallography, docking
Abstract: Peroxisome Proliferator Activated Receptors (PPARs) are a family of three related nuclear receptors first cloned in 1990. Their involvement in glucidic and lipidic homeostasis quickly made them an attractive target for the treatment of metabolic syndrome, the most prevalent mortality factor in developed countries. They therefore attracted much synthetical efforts, more particularly PPARγ. Supported by a large number of crystallographic studies, data derived from these compounds lead to a fairly clear view of the agonist binding mode into the Ligand Binding Domain (LBD). Nearly all the compounds conform to a three-module structure, with a binder group involved in a series of hydrogen bonds in front of the ligand-dependent Activation Function (AF2), a linker mostly arranged around a phenoxyethyl and an effector end occupying the large cavity of the binding site. Following the marketing of the glitazones and the observation of the hepatotoxicity of troglitazone, variations in the binder led to the glitazars, and then pharmacomodulations have been undertaken on the two other modules, leading to a large family of highly related chemical structures. Some compounds, while still adhering to the three-module structure, diverge from the mainstream, such as the phthalates. Curiously, these plasticizers were known to elicit biological effects that led to the discovery of PPARs but were not actively studied as PPARs agonists. As the biological effects of PPARs became clearer, new compounds were also found to exert at least a part of their actions by the activation of PPARγ.
Export Options
About this article
Cite this article as:
Farce A., Renault N. and Chavatte P., Structural Insight into PPARγ Ligands Binding, Current Medicinal Chemistry 2009; 16 (14) . https://dx.doi.org/10.2174/092986709788186165
DOI https://dx.doi.org/10.2174/092986709788186165 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
Current advances in inherited cardiomyopathy
Describe in detail all novel advances in multimodality imaging related to inherited cardiomyopathy diagnosis and prognosis. Shed light to deeper phenotypic characterization. Acknowledge recent advances in genetics, genomics and precision medicineread 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
-
Independent Relationship of Osteocalcin Circulating Levels with Obesity, Type 2 Diabetes, Hypertension, and HDL Cholesterol
Endocrine, Metabolic & Immune Disorders - Drug Targets Editorial (thematic Issue: Functional Performance of L-Carnosine (β-Alanyl-L-Histidine) and Related Imidazole-Containing Dipeptides. Design and Modern Applications of Drug Delivery Systems (Nanosuspensions of Nanosize Materials, Mucoadhesive Drug Delivery Systems, Formulations of Transdermal Patches for Controlled Drug Delivery)
Recent Patents on Drug Delivery & Formulation Biochemical, Biomedical and Metabolic Aspects of Imidazole-Containing Dipeptides with the Inherent Complexity to Neurodegenerative Diseases and Various States of Mental Well-Being: A Challenging Correction and Neurotherapeutic Pharmaceutical Biotechnology for Treating Cognitive Deficits, Depression and Intellectual Disabilities
Current Pharmaceutical Biotechnology Research Progress on Pathogenesis of Obesity-Induced Insulin Resistance and Its Therapeutic Targets: PPARα/γ
Current Signal Transduction Therapy MicroRNAs Determining Inflammation as Novel Biomarkers and Potential Therapeutic Targets
Current Medicinal Chemistry Role of Ischemia Modified Albumin Serum Levels as an Oxidative Stress Marker in Children with Diabetic Ketoacidosis
Combinatorial Chemistry & High Throughput Screening ABT-450: A Novel Protease Inhibitor for the Treatment of Hepatitis C Virus Infection
Current Medicinal Chemistry Phospholipid Transfer Protein in Diabetes, Metabolic Syndrome and Obesity
Cardiovascular & Hematological Disorders-Drug Targets Extrinsic Factors Promoting Insulin Producing Cell-Differentiation and Insulin Expression Enhancement-Hope for Diabetics.
Current Stem Cell Research & Therapy Pleiotropic Effects of Statins - Clinical Evidence
Current Pharmaceutical Design Lifestyle Interventions in Pregnancy: Myths and Facts, A Commentary
Current Women`s Health Reviews Withdrawal Notice: Clinical Pathways Optimization from Decision Rules Based on Fusion Stream Mining and Fuzzy Unordered Rule Induction Strategy in Diabetes Treatment
Current Bioinformatics Interaction between Thienopyridines and Proton Pump Inhibitors
Cardiovascular & Hematological Disorders-Drug Targets Chemokines in the Pathogenesis and as Therapeutical Markers and Targets of HCV Chronic Infection and HCV Extrahepatic Manifestations
Current Drug Targets Therapeutic Approaches for Reducing C-Reactive Protein (CRP) Levels and the Associated Cardiovascular Risk
Current Chemical Biology Clinical Applications of Autoimmunity to Citrullinated Proteins in Rheumatoid Arthritis, from Improving Diagnostics to Future Therapies
Recent Patents on Inflammation & Allergy Drug Discovery Crosstalk between Gut Microbiota and Central Nervous System: A Focus on Alzheimer's Disease
Current Alzheimer Research Vitamin D Metabolism Genes in Asthma and Atopy
Mini-Reviews in Medicinal Chemistry Genetic and Molecular Approaches to the Immunopathogenesis of Multiple Sclerosis: An Update
Current Molecular Medicine On the Involvement of H2S in Nitroso Signaling and Other Mechanisms of H2S Action
Current Pharmaceutical Biotechnology