Harmine and 7,8-dihydroxyflavone synergistically suitable for amyotrophic lateral sclerosis management: An in silico study

Q3 Pharmacology, Toxicology and Pharmaceutics
T. Fatoki, S. Chukwuejim, O. Ibraheem, Christiana Oke, Blessing Ejimadu, Isaiah Olaoye, Oluwabukola Oyegbenro, Taiwo Salami, R. Basorun, Oluwafisayomi Oluwadare, Yetunde Salawudeen
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引用次数: 6

Abstract

Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by progressive degeneration of both upper and lower motor neurons, resulting in paralysis and eventually leads to death from respiratory failure typically within 3 to 5 years of symptom onset. The aim of this work was to predict the pharmacokinetics and identify unique protein targets that are associated with potential anti-ALS phytochemicals and FDA-approved drugs, by in silico approaches. Materials and methods: Standard computational tools (webserver and software) were used, and the methods used are clustering analysis, pharmacokinetics and molecular target predictions, and molecular docking simulation. Results and discussion: The results show that riluzole, β-asarone, cryptotanshinone, harmine and 7,8-dihydroxyflavone have similar pharmacokinetics properties. Riluzole and harmine show 95% probability of target on norepinephrine transporter. Huperzine-A and cryptotanshinone show 100% probability of target on acetylcholinesterase. 7,8-dihydroxyflavone shows 35% probability of target on several carbonic anhydrases, 40% probability of target on CYP19A1, and 100% probability of target on inhibitor of nuclear factor kappa B kinase beta subunit and neurotrophic tyrosine kinase receptor type 2, respectively. Harmine also shows 95% probability of target on dual specificity tyrosine-phosphorylation-regulated kinases, threonine-protein kinases (haspin and PIM3), adrenergic receptors, cyclin-dependent kinases (CDK5 and CDK9), monoamine oxidase A, casein kinase I delta, serotonin receptors, dual specificity protein kinases (CLK1, CLK2, and CLK4), and nischarin, respectively. Also, the results of gene expression network show possible involvement of CDK1, CDK2, CDK4, ERK1, ERK2 and MAPK14 signaling pathways. This study shows that riluzole and harmine have closely similar physicochemical and pharmacokinetics properties as well as molecular targets, such as norepinephrine transporter (SLC6A2). Harmine, huperzine-A and cryptotanshinone could modulate acetylcholinesterase (AChE), which is involved in ALS-pathogenesis. The impact of 7,8-dihydroxyflavone on several carbonic anhydrases (CA) I, II, VII, IX, XII, and XIV, as well as CYP19A1, could help in remediating the respiratory failure associated with ALS. Conclusion: Overall, harmine is found to be superior to riluzole, and the combination of harmine with 7,8-dihydroxyflavone can provide more effective treatment for ALS than the current regime. Further work is needed to validate the predicted therapeutic targets of harmine identified in this study on ALS model or clinical trials, using in silico, in vitro and in vivo techniques. Graphical abstract:
Harmine和7,8-二羟黄酮协同适用于肌萎缩侧索硬化管理:一项计算机研究
简介:肌萎缩侧索硬化症(ALS)是一种致命的神经系统疾病,其特征是上下运动神经元进行性退化,导致瘫痪,并最终导致呼吸衰竭死亡,通常在症状出现后3至5年内死亡。这项工作的目的是通过计算机方法预测药代动力学,并确定与潜在的抗ALS植物化学物质和FDA批准的药物相关的独特蛋白质靶点。材料和方法:使用标准计算工具(网络服务器和软件),使用的方法包括聚类分析、药代动力学和分子靶标预测以及分子对接模拟。结果与讨论:结果表明,利鲁唑、β-细辛酮、隐丹参酮、骆驼蓬碱和7,8-二羟基黄酮具有相似的药代动力学性质。利鲁唑和骆驼蓬碱在去甲肾上腺素转运蛋白上显示95%的靶点概率。胡泛嗪-A和隐丹参酮对乙酰胆碱酯酶的靶向作用概率为100%。7,8-二羟基黄酮在几种碳酸酐酶上显示出35%的靶向概率,在CYP19A1上显示出40%的靶向可能性,在核因子κB激酶β亚基抑制剂和神经营养酪氨酸激酶受体2型上显示出100%的靶向几率。Harmine还显示95%的概率分别靶向双特异性酪氨酸磷酸化调节激酶、苏氨酸蛋白激酶(haspin和PIM3)、肾上腺素能受体、细胞周期蛋白依赖性激酶(CDK5和CDK9)、单胺氧化酶A、酪蛋白激酶Iδ、血清素受体、双特异性蛋白激酶(CLK1、CLK2和CLK4)和尼沙林。此外,基因表达网络的结果显示CDK1、CDK2、CDK4、ERK1、ERK2和MAPK14信号通路可能参与。本研究表明,利鲁唑和骆驼蓬碱具有非常相似的理化和药代动力学特性,以及分子靶标,如去甲肾上腺素转运蛋白(SLC6A2)。Harmine、huperzine-A和隐丹参酮可调节乙酰胆碱酯酶(AChE),后者参与ALS的发病机制。7,8-二羟基黄酮对几种碳酸酐酶(CA)I、II、VII、IX、XII和XIV以及CYP19A1的影响可能有助于治疗与ALS相关的呼吸衰竭。结论:总的来说,骆驼蓬碱优于利鲁唑,并且骆驼蓬碱与7,8-二羟基黄酮联合治疗ALS比现有方案更有效。需要进一步的工作来验证本研究中在ALS模型或临床试验中确定的骆驼蓬碱的预测治疗靶点,使用计算机、体外和体内技术。图形摘要:
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Research Results in Pharmacology
Research Results in Pharmacology Medicine-Pharmacology (medical)
CiteScore
1.50
自引率
0.00%
发文量
32
审稿时长
12 weeks
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