新型潜在的糜蛋白酶、脾脏酪氨酸激酶和前列腺素D2受体三效抑制剂治疗哮喘的最佳分子结合数据和药代动力学特征。

IF 3.6 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Journal, genetic engineering & biotechnology Pub Date : 2023-11-10 DOI:10.1186/s43141-023-00577-8
Precious Ayorinde Akinnusi, Samuel Olawale Olubode, Ayomide Oluwadarasimi Adebesin, Adebowale Abiodun Alade, Victor Chinedu Nwoke, Sidiqat Adamson Shodehinde
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引用次数: 0

摘要

背景:哮喘是一种影响气道的慢性复杂肺部疾病。每年共有250000例哮喘相关死亡记录,包括糜蛋白酶、脾脏酪氨酸激酶和前列腺素D2受体在内的几种蛋白质与哮喘的病理生理学有关。已经开发了不同的抗炎药来治疗哮喘,特别是皮质类固醇,但相关的不良反应不容忽视。因此,有兴趣鉴定和开发与哮喘相关的整体蛋白的小分子抑制剂,这些抑制剂几乎没有副作用。本文采用分子模拟方法筛选了臭蝶中的生物活性化合物,并鉴定了与蛋白质靶标具有高结合亲和力的化合物。结果:经过严格、精确的分子筛选,共鉴定出5个化合物,分别为(-)-表儿茶素、绿原酸、乌布碱、槲皮素和槲皮素3-O-芸香糖苷。这些化合物通常显示出与所有靶标的令人印象深刻的结合。然而,绿原酸、槲皮素和槲皮素3-O-芸香糖苷在三重作用抑制方面显示出更好的前景。进一步的肺部和口服药代动力学显示,所有报告的化合物都有阳性结果。生成的药效团模型显示氢键供体、氢键受体和芳香环是三重作用抑制所需的基本结构特征。结论:这些发现表明,这些化合物可以作为蛋白质靶标的三重作用抑制剂进行探索。因此,建议对其进行进一步分析。
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Optimal molecular binding data and pharmacokinetic profiles of novel potential triple-action inhibitors of chymase, spleen tyrosine kinase, and prostaglandin D2 receptor in the treatment of asthma.

Background: Asthma is a chronic and complex pulmonary condition that affects the airways. A total of 250,000 asthma-related deaths are recorded annually and several proteins including chymase, spleen tyrosine kinase, and prostaglandin D2 receptor have been implicated in the pathophysiology of asthma. Different anti-inflammatory drugs have been developed for the treatment of asthma, particularly corticosteroids, but the associated adverse reactions cannot be overlooked. It is therefore of interest to identify and develop small molecule inhibitors of the integral proteins associated with asthma that have very little or no side effects. Herein, a molecular modeling approach was employed to screen the bioactive compounds in Chromolaena odorata and identify compounds with high binding affinity to the protein targets.

Results: Five compounds were identified after rigorous and precise molecular screening namely (-)-epicatechin, chlorogenic acid, ombuine, quercetagetin, and quercetin 3-O-rutinoside. These compounds generally showed impressive binding to all the targets understudy. However, chlorogenic acid, quercetagetin, and quercetin 3-O-rutinoside showed better prospects in terms of triple-action inhibition. Further pulmonary and oral pharmacokinetics showed positive results for all the reported compounds. The generated pharmacophore model showed hydrogen bond donor, hydrogen bond acceptor, and aromatic rings as basic structural features required for triple action inhibition.

Conclusion: These findings suggest that these compounds could be explored as triple-action inhibitors of the protein targets. They are, therefore, recommended for further analysis.

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