Abstract

Parkinson’s disease is the second most common progressive neurodegenerative disorder, marked by the degeneration of dopaminergic neurons in the substantia nigra, leading to motor and non-motor impairments. Its etiology involves environmental toxins (pesticides, heavy metals, air pollutants), genetic mutations (LRRK2, SNCA, PARK2, PINK1, PARK7), oxidative stress, and mitochondrial dysfunction. Recent therapeutic strategies focus on neuroprotective agents that target oxidative stress and protein aggregation. Senescence Marker Protein30 (SMP30), also known as regucalcin, is an aging-related protein critical for antioxidative defense, calcium homeostasis, and neuronal survival. This study explores the potential of BL-918, along with gluconolactone and five control drugs (levodopa, carbidopa, ropinirole, pramipexole, amantadine), to enhance mouse SMP30 (Protein Data Bank Identifier [PDB ID]: 4GN7) structural modulation using in silico approaches. Molecular docking (AutoDock Vina) revealed BL-918 had the highest binding affinity (–10.2 kcal/mol). Molecular dynamics (GROMACS) demonstrated structural stability of the SMP30-BL-918 complex over 100 ns, supported by root mean square deviation (RMSD), radius of gyration (Rg), root mean square fluctuation (RMSF), and solvent accessible surface area (SASA) analyses. Hydrogen bonding was initially strong but transient. SwissADME and ProTox 3.0 characterized BL-918 as a viable therapeutic lead, outlining key pharmacokinetic targets for future optimization. Protein Contact Atlas and STRING analysis identified key non-covalent and protein-protein interactions. Due to BL-918’s low inhibition constant (Ki = 3.33 × 10–8 M), which indicates a high binding affinity, and its ADMET profile, it is suggested that BL-918 could potentially modulate SMP30 at the functional protein level. These strong initial docking interactions, despite exhibiting a decline in hydrogen bonds during molecular dynamics simulations, may lead to downstream regulatory effects that could be associated with increased expression of the SMP-30 protein, pending experimental validation.

Key words: Parkinson's Disease; SMP-30; BL-918; AutoDock Vina; GROMACS; Molecular Dynamics Simulation