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.

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 hypothesised 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 W. 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. Communicated by Ramaswamy H. Sarma.