Across the blood-brain barrier: Neurotherapeutic screening and characterization of naringenin as a novel CRMP-2 inhibitor in the treatment of Alzheimer's disease using bioinformatics and computational tools
Across the blood-brain barrier: Neurotherapeutic screening and characterization of naringenin as a novel CRMP-2 inhibitor in the treatment of Alzheimer's disease using bioinformatics and computational tools
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DOI：
10.1016/j.compbiomed.2018.05.012
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发表时间：
2018-07-01
影响因子：
7.7
通讯作者：
Soliman, Mahmoud E. S.
中科院分区：
文献类型：
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作者：
Lawal, Maryam;Olotu, Fisayo A.;Soliman, Mahmoud E. S.
中枢神经系统药物的发现和开发过程一直受到潜在药物分子无法通过血脑屏障（BBB）的限制。这给阿尔茨海默病（AD）等神经退行性疾病的治疗带来了重大挫折，因此需要能够严格遵守合适中枢神经系统药物选择标准的化合物。塌陷反应介质蛋白-2 （CRMP-2）最近被确定为神经治疗的可行靶点，因为它与阿尔茨海默病的病因有关。既往研究表明，Naringenin （NAR）是Drynaria rhizome （DR）提取物的小分子衍生物，可特异性结合CRMP-2并降低其磷酸化水平。这被证明可以促进轴突再生，提高认知和学习能力。在此，我们报告了首次使用化学信息学技术，使用选择性标准来定义NAR的中枢神经系统药物适用性，并结合可能的生物活性和毒性预测。此外，我们通过模拟其与人类CRMP-2 （hCRMP-2）的分子相互作用来评估NAR的机制活性。理化分析显示NAR作为一种中枢神经系统药物的适用性及其穿过血脑屏障的能力。还预测了可能的神经源性、抗癌和心脏保护活性。NAR与CRMP-2表现出良好的结合，并与活性位点残基形成强键，这是其稳定性和亲和力的原因。此外，NAR诱导了显著的CRMP-2构象变化，这种发生可能会破坏激酶介导的磷酸化。这些发现将有助于优化NAR并提高其治疗AD的神经治疗活性。
The discovery and developmental processes of CNS drugs have been limited by the inability of potential drug molecules to pass through the blood-brain barrier (BBB). This presents a significant setback in the treatment of neurodegenerative disorders such as Alzheimer's disease (AD), hence the need for compounds that can adhere strictly to the selective criteria of suitable CNS drugs. Collapsin response mediator protein-2 (CRMP-2) has been recently identified as a viable target in neurotherapeutics due to its involvement in the etiology of AD. As shown in previous studies, Naringenin (NAR), a small molecule derivative of Drynaria rhizome (DR) extract, specifically binds CRMP-2 and reduces its phosphorylation. This was shown to facilitate axonal regrowth, with improvement in cognition and learning. Herein, we report the first account of the use of cheminformatics techniques to define the CNS drug-suitability of NAR using selective criteria, coupled with the prediction of possible biological activities and toxicities. Also, we evaluated the mechanistic activity of NAR by modeling its molecular interaction with human CRMP-2 (hCRMP-2). Physicochemical analyses revealed the suitability of NAR as a CNS drug and its ability to transverse the BBB. Possible neurogenic, anti-carcinogenic and cardioprotective activities were also predicted. NAR exhibited favorable binding to CRMP-2 and formed strong bonds with active site residues, which accounts for its stabilization and affinity. Moreover, NAR induced notable conformational changes in CRMP-2, an occurrence that could possibly disrupt kinase-mediated phosphorylation. These findings will aid in the optimization of NAR and improve its neurotherapeutic activities in the treatment of AD.