Network metrics, structural dynamics and density functional theory calculations identified a novel Ursodeoxycholic Acid derivative against therapeutic target Parkin for Parkinson's disease

[Display omitted] •GIN analysis revealed PARK2, LRRK2, PARK7, PINK1 and SNCA as hub-genes.•Topologically favoured Parkin was considered as a therapeutic target.•ADMET screening identified a novel UDCA derivative as potential lead candidate.•Chemical reactivity and ligand stability were analysed through DFT simulation.•Docking and MDS established novel lead as potential Parkin inhibitor. Parkinson's disease (PD) has been designated as one of the priority neurodegenerative disorders worldwide. Although diagnostic biomarkers have been identified, early onset detection and targeted therapy are still limited. An integrated systems and structural biology approach were adopted to identify therapeutic targets for PD. From a set of 49 PD associated genes, a densely connected interactome was constructed. Based on centrality indices, degree of interaction and functional enrichments, LRRK2, PARK2, PARK7, PINK1 and SNCA were identified as the hub-genes. PARK2 (Parkin) was finalized as a potent theranostic candidate marker due to its strong association (score > 0.99) with α-synuclein (SNCA), which directly regulates PD progression. Besides, modeling and validation of Parkin structure, an extensive virtual-screening revealed small (commercially available) inhibitors against Parkin. Molecule-258 (ZINC5022267) was selected as a potent candidate based on pharmacokinetic profiles, Density Functional Theory (DFT) energy calculations (ΔE = 6.93 eV) and high binding affinity (Binding energy = -6.57 ± 0.1 kcal/mol; Inhibition constant = 15.35 µM) against Parkin. Molecular dynamics simulation of protein-inhibitor complexes further strengthened the therapeutic propositions with stable trajectories (low structural fluctuations), hydrogen bonding patterns and interactive energies (>0kJ/mol). Our study encourages experimental validations of the novel drug candidate to prevent the auto-inhibition of Parkin mediated ubiquitination in PD.