In silico and In vivo Evaluation of Oxidative Stress Inhibitors Against Parkinson's Disease using the C. elegans Model

Title:In silico and In vivo Evaluation of Oxidative Stress Inhibitors Against Parkinson's Disease using the C. elegans Model

Volume: 23 Issue: 8

Author(s): Pradeep Hanumanthappa, Arpitha Ashok, Inderjit Prakash, Carmel I. Priya, Julie Zinzala, Vidya V. Marigowda and Aparna H. Sosalegowda*

Affiliation:

• Department of Studies in Biotechnology, University of Mysore, Manasagangothri, Mysore 570 006, Karnataka,India

Keywords: Oxidative stress, Parkinson’s disease, Cullin-3, molecular dynamics, rosmarinic acid, C. elegans.

Abstract:

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: Our 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.

Cite this article as:

Hanumanthappa Pradeep , Ashok Arpitha , Prakash Inderjit , Priya I. Carmel , Zinzala Julie , Marigowda V. Vidya and Sosalegowda H. Aparna *, In silico and In vivo Evaluation of Oxidative Stress Inhibitors Against Parkinson's Disease using the C. elegans Model, Combinatorial Chemistry & High Throughput Screening 2020; 23 (8) . https://dx.doi.org/10.2174/1386207323666200514074128