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.

背景：帕金森氏病仅次于阿尔茨海默氏症，是主要的神经退行性疾病，目前尚无治愈或改善疾病的疗法。大量证据表明，PD表现为抗氧化机制受损导致神经元死亡的结果，其中Cullin-3已上升为涉及涉及抗氧化机制受损疾病的潜在治疗靶标。

目的：设计针对Cullin-3蛋白的靶标特异性抑制剂可能是提高Nrf2水平并降低“脱靶”毒性的可能性的有前途的策略。

方法：在本研究中，采用了一种综合的计算和湿实验室方法来鉴定Cullin-3的小分子抑制剂。合理的药物设计过程包括同源建模和Cullin-3药效团的推导，锌天然化合物数据库的虚拟筛选，分子对接和基于分子动力学的配体分子筛选。在秀丽隐杆线虫的PD模型中进行了鉴定的先导化合物的体内验证。

结果与讨论：我们的策略产生了一种潜在的抑制剂。（滑翔分数＝ -12.31），其在秀丽隐杆线虫PD模型中的神经保护功效进行了评估。该抑制剂能够有效防御秀丽隐杆线虫PD模型中的神经元死亡，并且其神经保护作用归因于其抗氧化活性，这由超氧化物歧化酶，过氧化氢酶的增加以及乙酰胆碱酯酶和活性氧种类水平的降低所支持。此外，Cullin-3抑制剂可显着恢复转基因秀丽隐杆线虫的行为缺陷。

结论：综上所述，这些发现强调了Cullin-3抑制作用可阻止PD持续性神经元死亡。专注于Cullin-3及其作用机制的进一步研究将很有趣。