Abstract
Vitamin-D deficiency is a global concern. Gene mutations in the vitamin D receptor’s (VDR) ligand binding domain (LBD) variously alter the ligand binding affinity, heterodimerization with retinoid X receptor (RXR) and inhibit coactivator interactions. These LBD mutations may result in partial or total hormone unresponsiveness. A plethora of evidence reports that selective long chain polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and arachidonic acid (AA) bind to the ligand-binding domain of VDR and lead to transcriptional activation. We, therefore, hypothesize that selective PUFAs would modulate the dynamics and kinetics of VDRs, irrespective of the deficiency of vitamin-D. The spatial arrangements of the selected PUFAs in VDR active site were examined by in-silico docking studies. The docking results revealed that PUFAs have fatty acid structure-specific binding affinity towards VDR. The calculated EPA, DHA & AA binding energies (Cdocker energy) were lesser compared to vitamin-D in wild type of VDR (PDB id: 2ZLC). Of note, the DHA has higher binding interactions to the mutated VDR (PDB id: 3VT7) when compared to the standard Vitamin-D. Molecular dynamic simulation was utilized to confirm the stability of potential compound binding of DHA with mutated VDR complex. These findings suggest the unique roles of PUFAs in VDR activation and may offer alternate strategy to circumvent vitamin-D deficiency.
Keywords: Vitamin D, Eicosapentaenoic acid, Docosahexaenoic acid, arachidonic acid, Vitamin-D receptor, Type 2 diabetes mellitus.
Mini-Reviews in Medicinal Chemistry
Title:Distinct Modulation of Wild-Type and Selective Gene Mutated Vitamin D Receptor by Essential Polyunsaturated Fatty Acids
Volume: 21 Issue: 17
Author(s): Hari Balaji, A. Selvaraj, Niladri Saha, P. Shyam Sundar, S. Jubie and Suresh K. Mohankumar*
Affiliation:
- TIFAC CORE in Herbal Drugs, Department of Pharmacognosy, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamil nadu,India
Keywords: Vitamin D, Eicosapentaenoic acid, Docosahexaenoic acid, arachidonic acid, Vitamin-D receptor, Type 2 diabetes mellitus.
Abstract: Vitamin-D deficiency is a global concern. Gene mutations in the vitamin D receptor’s (VDR) ligand binding domain (LBD) variously alter the ligand binding affinity, heterodimerization with retinoid X receptor (RXR) and inhibit coactivator interactions. These LBD mutations may result in partial or total hormone unresponsiveness. A plethora of evidence reports that selective long chain polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and arachidonic acid (AA) bind to the ligand-binding domain of VDR and lead to transcriptional activation. We, therefore, hypothesize that selective PUFAs would modulate the dynamics and kinetics of VDRs, irrespective of the deficiency of vitamin-D. The spatial arrangements of the selected PUFAs in VDR active site were examined by in-silico docking studies. The docking results revealed that PUFAs have fatty acid structure-specific binding affinity towards VDR. The calculated EPA, DHA & AA binding energies (Cdocker energy) were lesser compared to vitamin-D in wild type of VDR (PDB id: 2ZLC). Of note, the DHA has higher binding interactions to the mutated VDR (PDB id: 3VT7) when compared to the standard Vitamin-D. Molecular dynamic simulation was utilized to confirm the stability of potential compound binding of DHA with mutated VDR complex. These findings suggest the unique roles of PUFAs in VDR activation and may offer alternate strategy to circumvent vitamin-D deficiency.
Export Options
About this article
Cite this article as:
Balaji Hari , Selvaraj A. , Saha Niladri, Sundar Shyam P., Jubie S. and Mohankumar K. Suresh *, Distinct Modulation of Wild-Type and Selective Gene Mutated Vitamin D Receptor by Essential Polyunsaturated Fatty Acids, Mini-Reviews in Medicinal Chemistry 2021; 21 (17) . https://dx.doi.org/10.2174/1389557521666210104170408
DOI https://dx.doi.org/10.2174/1389557521666210104170408 |
Print ISSN 1389-5575 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5607 |
Call for Papers in Thematic Issues
Bioprospecting of Natural Products as Sources of New Multitarget Therapies
According to the Convention on Biological Diversity, bioprospecting is the exploration of biodiversity and indigenous knowledge to develop commercially valuable products for pharmaceutical and other applications. Bioprospecting involves searching for useful organic compounds in plants, fungi, marine organisms, and microorganisms. Natural products traditionally constituted the primary source of more than ...read more
Computational Frontiers in Medicinal Chemistry
The thematic issue "Computational Frontiers in Medicinal Chemistry" provides a robust platform for delving into state-of-the-art computational methodologies and technologies that significantly propel advancements in medicinal chemistry. This edition seeks to amalgamate top-tier reviews spotlighting the latest trends and breakthroughs in the fusion of computational approaches, including artificial intelligence (AI) ...read more
Drugs and mitochondria
Mitochondria play a central role in the life and death of cells. They are not merely the center for energy metabolism but are also the headquarters for different catabolic and anabolic processes, calcium fluxes, and various signaling pathways. Mitochondria maintain homeostasis in the cell by interacting with reactive oxygen-nitrogen species ...read more
Mitochondria as a Therapeutic Target in Metabolic Disorders
Mitochondria are the primary site of adenosine triphosphate (ATP) production in mammalian cells. Moreover, these organelles are an important source of reactive oxygen and nitrogen species in virtually any nucleated cell type. The modulation of a myriad of cellular signaling pathways depends on the mitochondrial physiology. Mitochondrial dysfunction is observed ...read more
![](/images/wayfinder.jpg)
- 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
Related Articles
-
The Anti-Inflammatory Effects of Statins on Coronary Artery Disease: An Updated Review of the Literature
Current Cardiology Reviews Genetic and Molecular Approaches to the Immunopathogenesis of Multiple Sclerosis: An Update
Current Molecular Medicine Physico-Chemical Properties Mediating Reproductive and Developmental Toxicity of Engineered Nanomaterials
Current Medicinal Chemistry Biologics and the Cardiovascular System: A Double-Edged Sword
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry C-Reactive Protein and Asymmetric Dimethylarginine: Markers or Mediators in Cardiovascular Disorders?
Current Pharmaceutical Design Inhibitors of Dipeptidyl Peptidase IV - Recent Advances and Structural Views
Current Topics in Medicinal Chemistry Editorial (Thematic Issue: Endothelium: A Target for Therapeutic Intervention)
Current Vascular Pharmacology Mangiferin – a Bioactive Xanthonoid, not only from Mango and not just Antioxidant
Mini-Reviews in Medicinal Chemistry Potential Impact of Genetic Variants in Nrf2 Regulated Antioxidant Genes and Risk Prediction of Diabetes and Associated Cardiac Complications
Current Medicinal Chemistry Targeting the Arrhythmogenic Substrate in Atrial Fibrillation: Focus on Structural Remodeling
Current Drug Targets Drug Repurposing: An Emerging Tool for Drug Reuse, Recycling and Discovery
Current Drug Research Reviews Patent Annotations
Recent Patents on CNS Drug Discovery (Discontinued) Sensors Based On Carbon Nanotubes and Their Applications: A Review
Current Nanoscience Molecular Determinants of the Cardiometabolic Phenotype
Endocrine, Metabolic & Immune Disorders - Drug Targets Protein Oxidative Modification in the Aging Organism and the Role of the Ubiquitin Proteasomal System
Current Pharmaceutical Design Ageing as a Trait de Union Between Diabetes and Dementia for Frailty
CNS & Neurological Disorders - Drug Targets Preeclampsia: A Couples Disease with Maternal and Fetal Manifestations
Current Pharmaceutical Design The Future of Continuous Glucose Monitoring: Closed Loop
Current Diabetes Reviews The Forkhead Transcription Factor FOXO3a Controls Microglial Inflammatory Activation and Eventual Apoptotic Injury through Caspase 3
Current Neurovascular Research Regression of Oxidative Stress by Targeting eNOS and Nrf2/ARE Signaling: A Guided Drug Target for Cardiovascular Diseases
Current Topics in Medicinal Chemistry