Jul 2026· Journal of Applied Pharmaceutical Sciences· Vol 16, pp. 953 - 966· 0 citations· 64 references
TL;DR
It is suggested that BL-918 could potentially modulate SMP30 at the functional protein level, and SwissADME and ProTox 3.0 characterized BL-918 as a viable therapeutic lead, outlining key pharmacokinetic targets for future optimization.
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.
This review focuses on the potential molecular mechanism underlying KLF4-mediated neuroinflammation, oxidative stress, mitochondrial dysfunction, and apoptosis and targeting them appears to be a viable therapeutic strategy for treating PD.
Anjali Kumari, K. Aran· Current Medical Science· 0 citations
BACKGROUND
Parkinson's disease (PD) is a prevalent neurodegenerative disorder hallmarked by progressive loss of midbrain dopaminergic (DA) neurons, neurite atrophy, neurotransmitter imbalance, and motor dysfunction. Therapeutic strategies targeting neuronal integrity and neuroinflammation hold translational value beyond conventional symptomatic therapies for PD. Sarsasapogenin, a natural steroidal saponin, exhibits documented neuroprotective properties in multiple neurological diseases. However, its therapeutic potential and underlying mechanisms in PD remain to be elucidated.
METHODS
The neuroprotective efficacy of sarsasapogenin was assessed in a subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse PD model and 1-methyl-4-phenylpyridinium ion (MPP+)-insulted primary cortical and dopaminergic neuronal cultures. Motor function was evaluated via a variety of behavioral tests. Survival of dopaminergic neurons was quantified using tyrosine hydroxylase (TH) immunostaining. Levels of monoamine neurotransmitters and their metabolites were measured using high-performance liquid chromatography (HPLC), while serum proinflammatory cytokines were determined using enzyme-linked immunosorbent assay (ELISA). Neurite outgrowth and neuronal viability were examined under both preventive and therapeutic treatment regimens in vitro. Potential molecular targets of sarsasapogenin were screened and identified via Drug Affinity Responsive Target Stability (DARTS) coupled with molecular docking.
RESULTS
Twenty-one-day sarsasapogenin intervention mitigated aberrant motor deficits in MPTP-treated mice, rescued TH+ dopaminergic neurons in the substantia nigra, restored homeostasis of dopamine and norepinephrine, normalized the turnover of monoamines, and decreased peripheral levels of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). In primary neuronal cultures, sarsasapogenin significantly ameliorated MPP+-triggered neurite atrophy and neuronal loss in both cortical and ventral mesencephalic dopaminergic neurons. DARTS screening combined with molecular docking identified serpin family H member 1 (Serpin) H1 as a candidate binding protein of sarsasapogenin, with a favorable binding affinity of -8.6 kcal/mol.
CONCLUSIONS
Sarsasapogenin exerts comprehensive neuroprotective effects in preclinical PD models via synergistic modulation of dopaminergic neuronal survival, neurotransmitter balance, inflammatory inhibition, and neurite outgrowth. These findings highlight sarsasapogenin as a promising multi-target candidate for PD intervention, whereas the precise functional role of Serpin H1 in mediating its neuroprotective actions warrants further in-depth investigation.
Wendi Deng, Jinfeng Hong, Weixia Li et al.· Journal of Integrative Neuro...· 0 citations
Recent advances in multitarget drug development for AD and PD targeting compounds targeting Aβ, BACE1, MAO-B, cholinesterases, metal-ion dyshomeostasis, oxidative stress, and inflammatory pathways are reviewed.
Azmatullah Khan, Abdullah Abdullah, Syeda Farwa Naqvi et al.· Zeitschrift für Naturforschu...· 0 citations
Natural bioactive compounds, gene-based therapies, stem cell-based therapies, stem cell-based therapies, and nanotechnology-assisted drug delivery systems are promising alternatives as suggested by recent advances and could help to more effectively and permanently manage PD.
S. Arbab, Hanif Ullah, Yanting Han et al.· Ageing Research Reviews· 0 citations
Combined in silico and experimental findings highlight hesperidin’s strong binding to key molecular targets, whereas experimental evidence also confirms its antioxidant, anti-inflammatory, and anti-apoptotic effects, supporting its potential as a disease-modifying candidate in PD therapy.
Seyawash Ghani, Diksha Dalal, Anish Singh et al.· Current Behavioral Neuroscie...· 0 citations
Findings support the protective potential of RTA-408 in SCA3-related models and show its effects were associated with activation of Nrf2-related antioxidant responses, p62 upregulation, and selected improvements in mitochondrial phenotypes.
Shin-Hung Pan, Juichih Chang, Wan-Hsuan Lin et al.· Frontiers in Pharmacology· 0 citations
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