整合转录组学与疾病基因网络和EGFR激酶靶点的鉴定:通过虚拟筛选天然化合物发现脑癌治疗抑制剂。

IF 2.7 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Mohd Rehan, Wejdan M AlZahrani, Firoz Ahmed, Mohammad Imran Khan, Hifzur Rahman Ansari, Shazi Shakil, Moustafa E El-Araby, Salman Hosawi, Mohammad Saleem
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引用次数: 0

摘要

脑癌是一种高度侵袭性的恶性肿瘤,预后具有挑战性,治疗方案有限。采用先进的分析方法,包括激酶富集分析和疾病-基因网络整合,该研究确定EGFR是脑癌的关键治疗靶点。EGFR在细胞功能中起着关键作用,在各种癌症(尤其是脑癌)中都有升高,因此可以使用厄洛替尼和吉非替尼等小分子抑制剂。尽管结果令人鼓舞,但诸如耐药性和不良反应等挑战需要探索替代疗法。天然化合物显示出显著的致癌潜力,但毒性很小。因此,我们探索了EGFR激酶抑制剂的天然化合物数据库。利用分子对接和动态模拟,我们的研究确定了五种天然化合物——胞胆碱、西洛多辛、桂皮苷I、卡奈替尼和牛磺酸去氧胆酸——作为潜在的EGFR激酶抑制剂。对其结合属性的详细探索,包括位姿、相互作用残基、分子相互作用、动态行为和预测结合能,以及与天然抑制剂的比较,强调了它们的潜力。值得注意的是,在筛选的五种天然化合物中,卡奈替尼是一种已知的EGFR激酶共价抑制剂。然而,其具体的结合姿势仍未被探索。因此,为了揭示精确的结合方向,我们对卡尼替尼进行了共价对接模拟。此外,值得注意的是,这五种化合物都能穿透血脑屏障,符合到达大脑的基本标准。我们期望这项研究将为实验室的实验测试提供有价值的线索,推进脑癌治疗的前景。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Integrating transcriptomics with disease-gene network and identification of EGFR kinase target: inhibitor discovery through virtual screening of natural compounds for brain cancer therapy.

Brain cancer represents a highly aggressive malignant tumor with a challenging prognosis and limited treatment options. Employing advanced analytical methods, including Kinase Enrichment Analysis and Disease-Gene Network integration, the research identifies EGFR as a crucial therapeutic target for brain cancer. EGFR, a key player in cellular functions and elevated in various cancers, particularly brain cancer, is targeted using small molecule inhibitors like erlotinib and gefitinib. Despite promising results, challenges such as drug resistance and adverse effects necessitate exploration of alternative therapies. Natural compounds show significant potential for cancer with minimal associated toxicity. Thus, the natural compounds database was explored for EGFR kinase inhibitors. Utilizing molecular docking and dynamic simulation, our study identified five natural compounds-citicoline, silodosin, picroside I, canertinib, and tauroursodeoxycholic acid-as potential EGFR kinase inhibitors. Detailed exploration of their binding attributes, including pose, interacting residues, molecular interactions, dynamic behavior, and predicted binding energy, along with comparisons to the native inhibitor, underscored their potential. Notably, among the five natural compounds screened, canertinib is a known covalent inhibitor of EGFR kinase. However, its specific binding pose remains unexplored. Thus, to uncover the precise binding orientation, covalent docking simulation for canertinib was conducted. Additionally, it is noteworthy that all the five proposed compounds predicted to penetrate the blood-brain barrier, meeting the essential criteria for reaching brain. We anticipate that this study will provide valuable leads for experimental testing in the laboratory, advancing the prospects of brain cancer management.

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来源期刊
Journal of Biomolecular Structure & Dynamics
Journal of Biomolecular Structure & Dynamics 生物-生化与分子生物学
CiteScore
8.90
自引率
9.10%
发文量
597
审稿时长
2 months
期刊介绍: The Journal of Biomolecular Structure and Dynamics welcomes manuscripts on biological structure, dynamics, interactions and expression. The Journal is one of the leading publications in high end computational science, atomic structural biology, bioinformatics, virtual drug design, genomics and biological networks.
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