FROM MOLECULAR DOCKING TO NEUROPROTECTION: HARNESSING IN SILICO APPROACHES FOR THE DISCOVERY OF DJ-1 MODULATORS IN PARKINSON’S DISEASE THERAPEUTICS

Abstract

AIM- This study aims to attain novel therapeutics for potentially preventing the advancement (progression) and possibly the onset initiation of Parkinson’s disease through curbing reactive oxygen species with the help of a protein DJ-1. Parkinson’s disease (PD), a neurodegenerative disorder driven by oxidative stress and mitochondrial dysfunction, lacks disease-modifying therapies. DJ-1 (PARK7), a redox-sensitive chaperone protein, emerges as a critical neuroprotectant, with its conserved Cys106 residue acting as a sensor of oxidative damage. Overoxidation of Cys106 to sulfonic acid (Cys106-SO₃H) inactivates DJ-1, exacerbating α-synuclein aggregation, ROS accumulation, and dopaminergic neuron loss. This thesis integrates computational strategies to identify novel DJ-1 modulators that stabilize its redox-active state, counteracting PD progression. Using the DJ-1 crystal structure (PDB: 1SOA), refined via PyMOL to remove solvents and optimize stability, we performed structure-based virtual screening with SwissSimilarity, leveraging the known ligand UCP0054278 to identify 400 analogs form DrugBank. Sequential ADME/toxicity filtering (BBB permeability, Lipinski’s rule-of-five, PAINS, Brenks) prioritized 121 candidates, which were docked against DJ-1’s active site using AutoDock Vina. Top-scoring ligands (< -7.3 kcal/mol) revealed hydrogen bonding with Cys106, Glu18, and Met26-residues critical for DJ-1’s chaperone function. Discovery Studio visualization highlighted hydrophobic interactions stabilizing the oxidized sulfinic state (Cys106-SO₂H), preventing irreversible overoxidation. RESULS- Our results identified 19 lead compounds with potential to enhance DJ-1’s antioxidant capacity, mitochondrial stabilization, and α-synuclein disaggregation. Challenges, including DJ-1’s shallow binding pocket and dynamic redox transitions, were addressed through hybrid screening. Lead candidates, exhibited promise in silico, with potential for BBB penetration and minimal off-target effects. CONCLUSION- This work underscores DJ-1’s druggability and provides a roadmap for developing redox specific modulators. By preserving DJ-1’s neuroprotective functions, these molecules offer a paradigm shift from symptomatic L-DOPA treatments to disease-modifying therapies, addressing PD’s root pathological mechanisms. Future validation in in vitro and in vivo models will bridge computational insights to therapeutic innovation, advancing PD drug discovery. This abstract synthesizes structural biology, cheminformatics, and neurobiology to frame DJ-1 as a linchpin in PD therapeutics, highlighting the transformative potential of computational approaches in neurodegeneration research.