Mechanistic insights into the role of vitamin D and computational identification of potential lead compounds for Parkinson's disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder that affects dopaminergic neurons in the midbrain. A recent study suggests that Orphan Nuclear Receptor 1 (NURR1) impairment may contribute to PD pathogenesis. Our study found three potent agonists for NURR1 protein based on structural and ligand-based screening methods. The pharmacophore is comprised of a hydrogen bond donor, a hydrophobic group, and two aromatic rings (DHRR). The Pharmacophore screening method screened 3142 compounds, of which 3 were screened using structure-based screening. An analysis of the molecules using Molecular Mechanics-Generalized Born Surface Area (binding free energy) revealed a range of −46.77 to −59.06 Kcal/mol. After that, chemical reactivity was investigated by density functional theory, and molecular dynamics simulation was performed (protein-ligand stability). Based on the computational studies, Lifechemical_16901310, Maybridge_2815310, and NPACT_392450 are promising agonists with respect to NURR1. To confirm the potency of the identified compounds, further validation and experiments must be conducted.