Discovery of Novel Peroxisome Proliferator-Activated Receptor α (PPARα) Agonists by Virtual Screening and Biological Evaluation

2020 ◽  
Vol 60 (3) ◽  
pp. 1717-1727
Author(s):  
Liang Dai ◽  
Zhiqi Feng ◽  
Rili Zha ◽  
Keguang Cheng ◽  
Xiaoan Wen ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Biological Evaluation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

scholarly journals Development of a Protocol for Virtual Screening of PPARγ Weak Partial Agonists and Their Metabolites: Case Study on Naturally-derived Oleanane Triterpenoids

2021 ◽  
Vol 25 (2) ◽  
pp. 117-132
Author(s):  
Merilin Al Sharif ◽  
◽  
Petko Alov ◽  
Vessela Vitcheva ◽  
Antonia Diukendjieva ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Molecular Mechanisms ◽  
Partial Agonist ◽  
Mechanistic Explanation ◽  
Binding Mode ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Partial Agonists ◽  
Docking Protocol ◽  
Agonistic Activity

Triterpenoids are well known metabolic syndrome (MetS) modulators. One of the suggested molecular mechanisms of action involves peroxisome proliferator-activated receptor gamma (PPARγ) activation. In this study we aimed to: (i) develop a virtual screening (VS) protocol for PPARγ weak partial agonists, (ii) predict potential metabolic transformations of naturally-derived triterpenoids, and (iii) perform VS of the triterpenoids and their metabolites. The NIH PubMed system was searched for publications about naturally-derived oleanane triterpenoids which are agonists or up-regulators of PPARγ. Structure- and ligand-based methods were combined in the development of the VS protocol. Metabolites were predicted using Meteor Nexus expert system (Lhasa Limited). Two in-house virtual libraries of PPARγ weak partial agonists and naturally-derived triterpenoids with their predicted metabolites were compiled. The pharmacophore-based docking protocol was applied for VS of the collected triterpenoids. Most of the docking poses reproduced the binding mode of caulophyllogenin (a weak partial agonist) in a complex with PPARγ (PDB ID 5F9B). Our results contribute to the mechanistic explanation of the effects of triterpenoids suggesting possible weak partial agonistic activity toward PPARγ. This research can direct further studies on triterpenoids’ role in MetS modulation. The developed protocol can be applied for VS of any PPARγ weak partial agonists.

scholarly journals Synthesis, Characterization and Biological Evaluation of Thiazolidinedione Derivative as Novel Antidiabetic Agents

2021 ◽  
pp. 123-133
Author(s):  
Shivkant Patel ◽  
Ashim Kumar Sen ◽  
Dillip Kumar Dash ◽  
Piyushkumar Sadhu ◽  
Mamta Kumari ◽  
...  
Keyword(s):  
Biological Evaluation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Chemical Structures ◽  
Insulin Sensitizers ◽  
Diabetes Model ◽  
Glucose Synthesis ◽  
Sucrose Loading ◽  
Derivatives Of

Thiazolidinedione derivative have Antihyperglycemic activity, they are agonists for the peroxisome proliferator-activated receptor (PPAR), which controls glucose synthesis, transport, and utilization via regulating the transcription of insulin-responsive genes. A number of novel insulin sensitizers are currently being researched. Several of these are derivatives of Thiazolidinedione, but others have different chemical structures. In this work, we created some new Thiazolidinedione derivative based on structure–activity relationship as closely as feasible. The Thiazolidine-2,4-Dione derivatives were manually developed and synthesized using the proper synthetic techniques, then tested in vitro for antihyperglycemic action using the Sucrose loading model (SLM) and the Alloxan induced diabetes model (AIDM). The newly synthesized Thiazolidine-2,4-Dione derivative was characterized using infrared (IR) and proton (H) nuclear magnetic resonance. In this study we found that Compound M-4 has a lot of antihyperglycemic action, thus it's a good idea to think about using it as a lead material for the creation of anti-diabetic drugs.

scholarly journals Virtual Screening as a Technique for PPAR Modulator Discovery

PPAR Research ◽  
2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Stephanie N. Lewis ◽  
Josep Bassaganya-Riera ◽  
David R. Bevan
Keyword(s):  
Virtual Screening ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Effective Means ◽  
Binding Activity ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Compound Libraries ◽  
Computational Screening ◽  
Reporter Assays

Virtual screening (VS) is a discovery technique to identify novel compounds with therapeutic and preventive efficacy against disease. Our current focus is on the in silico screening and discovery of novel peroxisome proliferator-activated receptor-gamma (PPARγ) agonists. It is well recognized that PPARγagonists have therapeutic applications as insulin sensitizers in type 2 diabetes or as anti-inflammatories. VS is a cost- and time-effective means for identifying small molecules that have therapeutic potential. Our long-term goal is to devise computational approaches for testing the PPARγ-binding activity of extensive naturally occurring compound libraries prior to testing agonist activity using ligand-binding and reporter assays. This review summarizes the high potential for obtaining further fundamental understanding of PPARγbiology and development of novel therapies for treating chronic inflammatory diseases through evolution and implementation of computational screening processes for immunotherapeutics in conjunction with experimental methods for calibration and validation of results.

scholarly journals Synthesis and Biological Evaluation of 2-Heteroarylthioalkanoic Acid Analogues of Clofibric Acid as Peroxisome Proliferator-Activated Receptor α Agonists

2009 ◽  
Vol 52 (20) ◽  
pp. 6224-6232 ◽  
Author(s):  
Letizia Giampietro ◽  
Alessandra Ammazzalorso ◽  
Antonella Giancristofaro ◽  
Fabio Lannutti ◽  
Giancarlo Bettoni ◽  
...  
Keyword(s):  
Biological Evaluation ◽  
Clofibric Acid ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Synthesis And Biological Evaluation

scholarly journals Computational identification of potential chemoprophylactic agents according to dynamic behavior of peroxisome proliferator-activated receptor gamma

RSC Advances ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 147-159
Author(s):  
Zhiwei Yang ◽  
Yizhen Zhao ◽  
Dongxiao Hao ◽  
He Wang ◽  
Shengqing Li ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Dynamic Behavior ◽  
Screening Procedure ◽  
Peroxisome Proliferator ◽  
Targeted Therapeutics ◽  
Peroxisome Proliferator Activated Receptor ◽  
New Strategy ◽  
Conformational Plasticity ◽  
Computational Identification

Offering a new strategy for resurrecting PPARγ-targeted therapeutics to chemoprevention, by taking the conformational plasticity of the receptor into account in the virtual screening procedure.

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