4 research outputs found
Computational Prediction of a Putative Binding Site on Drp1: Implications for Antiparkinsonian Therapy
Parkinson’s
disease is the second most common neurodegenerative disorder, for
which no cure or disease-modifying therapies exist. It is evident
that mechanisms impairing mitochondrial dynamics will damage cell
signaling pathways, leading to neuronal death that manifests as Parkinson’s
disease. Dynamin related protein1, a highly conserved profission protein
that catalyzes the process of mitochondrial fission, is also associated
with the excessive fragmentation of mitochondria, impaired mitochondrial
dynamics and cell death. Hence, Dynamin related protein1 has emerged
as a key therapeutic target for diseases involving mitochondrial dysfunction.
In this work, we employed a relatively novel and integrated computational
strategy to identify a cryptic binding site of Dynamin related protein1
and exploited the predicted site in the rational drug designing process.
This novel approach yielded three potential inhibitors, and all of
them were evaluated for their neuroprotective efficacy in <i>C. elegans</i> model of Parkinson’s disease
In silico and In vivo Evaluation of Oxidative Stress Inhibitors Against Parkinson's Disease using the C. elegans Model
Background: Parkinson's disease ranks second, after Alzheimer's as the major neurodegenerative disorder, for which no cure or disease-modifying therapies exist. Ample evidence indicate that PD manifests as a result of impaired anti-oxidative machinery leading to neuronal death wherein Cullin-3 has ascended as a potential therapeutic target for diseases involving damaged anti-oxidative machinery. Objective: The design of target specific inhibitors for the Cullin-3 protein might be a promising strategy to increase the Nrf2 levels and to decrease the possibility of ``off-target'' toxic properties. Methods: In the present study, an integrated computational and wet lab approach was adopted to identify small molecule inhibitors for Cullin-3. The rational drug designing process comprised homology modeling and derivation of the pharmacophore for Cullin-3, virtual screening of Zinc natural compound database, molecular docking and Molecular dynamics based screening of ligand molecules. In vivo validations of an identified lead compound were conducted in the PD model of C. elegans. Results and Discussion: Chu center dot strategy yielded a potential inhibitor; (Glide score = -12.31), which was evaluated for its neuroprotective efficacy in the PD model of C. elegans. The inhibitor was able to efficiently defend against neuronal death in PD model of C. elegans and the neuroprotective effects were attributed to its anti-oxidant activities, supported by the increase in superoxide dismutase, catalase and the diminution of acetylcholinesterase and reactive oxygen species levels. In addition, the Cullin-3 inhibitor significantly restored the behavioral deficits in the transgenic C. elegans. Conclusion: Taken together, these findings highlight the potential utility of Cullin-3 inhibition to block the persistent neuronal death in PD. Further studies focusing on Cullin-3 and its mechanism of action would be interesting