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
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.