PUBLICATION
Understanding ligands driven mechanism of wild and mutant Aryl Hydrocarbon Receptor in presence of phytochemicals combating Parkinson's disease: An in silico and in vivo study
- Authors
- Narayan Rath, S., Jena, L., Patri, M.
- ID
- ZDB-PUB-190308-3
- Date
- 2019
- Source
- Journal of biomolecular structure & dynamics 38(3): 807-826 (Journal)
- Registered Authors
- Keywords
- Molecular Dynamics simulation, Parkinson?s disease, aryl hydrocarbon receptor, phytochemicals, virtual screening
- MeSH Terms
-
- Computer Simulation*
- Molecular Docking Simulation
- Hydrogen Bonding
- Protein Binding
- Phytochemicals/chemistry
- Phytochemicals/pharmacology
- Phytochemicals/therapeutic use*
- Parkinson Disease/drug therapy*
- Amino Acid Sequence
- Zebrafish
- Brain/drug effects
- Brain/enzymology
- Animals
- Protein Structure, Secondary
- Mutant Proteins/chemistry
- Mutant Proteins/metabolism*
- Ligands
- Cytochrome P-450 CYP1A1/metabolism
- Humans
- Drug Evaluation, Preclinical
- Protein Stability
- Protein Domains
- Receptors, Aryl Hydrocarbon/chemistry
- Receptors, Aryl Hydrocarbon/metabolism*
- Protein Interaction Maps
- PubMed
- 30836878 Full text @ J. Biomol. Struct. Dyn.
Citation
Narayan Rath, S., Jena, L., Patri, M. (2019) Understanding ligands driven mechanism of wild and mutant Aryl Hydrocarbon Receptor in presence of phytochemicals combating Parkinson's disease: An in silico and in vivo study. Journal of biomolecular structure & dynamics. 38(3):807-826.
Abstract
Aryl Hydrocarbon Receptor (AhR) is a key player to regulate the expression of a group of enzymes known as cytochrome P450s (CYPs) super family (CYP1A1, CYP1B1, CYP2B6, and CYP2E1) which metabolites diverse endogenous as well as toxic compounds such as Benzo[a] Pyrene (B[a] P) and TCDD. B[a] P induces oxidative stress and causes degeneration of dopaminergic neurons in the midbrain, may leads to Parkinson's disease (PD). The metabolism of B[a] P through the expression of CYPs is mainly triggered after binding of B[a] P within ligand binding domain of AhR. But, the molecular mechanism of AhR mediated xenobiotic metabolism in presence of diverse phytochemicals is yet to be studied. The solved AhR (PDB ID: 5NJ8, 23-273aa) structure lacks information for ligand binding domain therefore both wild type and mutant models were predicted and screened virtually against sixty one natural compounds. The result proposed withaferin A, withanolide A, withanolide B, withanolide D and withanone of plant Withania Somnifera as efficient ligand against both wild type and mutants (V381A and V381D) AhR models. However, in silico studies hypothesized withanolide A as a potent phytochemical to trigger the AhR mediated gene regulation activity of CYPs. The in vivo study in zebra fish model proposed about the neuro protective role of Withania Somnifera leaf extract in presence of B[a]P. The present study would throw lights on the molecular mechanism of phytochemicals mediated AhR activity which may be useful in treatment of PD.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping