通过硅学筛选、ADMET、动力学模拟和 DFT 分析,揭示从 Moringa oleifera 中提取的植物化合物作为非小细胞肺癌表皮生长因子受体(T790M/C797S)和血管内皮生长因子受体-2 的双重抑制剂的前景

IF 3.5 Q3 Biochemistry, Genetics and Molecular Biology Journal of Genetic Engineering and Biotechnology Pub Date : 2024-08-12 DOI:10.1016/j.jgeb.2024.100406
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引用次数: 0

摘要

非小细胞肺癌(NSCLC)是全球癌症死亡的主要原因之一,男女患者均可患病。目前的治疗方法主要是针对表皮生长因子受体(EGFR)的酪氨酸激酶抑制剂(TKIs)。然而,表皮生长因子受体 T790M 和 C797S 突变以及血管内皮生长因子受体-2 的上调等耐药机制往往会阻碍 TKIs 的疗效。因此,表皮生长因子受体(EGFR)和血管内皮生长因子受体(VEGFR)-2为通过开发双效药物治疗NSCLC提供了一个令人感兴趣的机会。本研究旨在评估有效阻断这两种受体的未来辣木(Moringa oleifera L. (MO))原生化合物。在我们的研究中,我们筛选了一个包含 200 种化合物的化合物库,这些化合物均来自以其卓越的治疗潜力而闻名的 Moringa oleifera L. 植物。我们发现了五种令人感兴趣的植物化合物:橙皮素、格丝菌素、槲皮素、没食子素和表没食子素,它们都是潜在的抗癌药物。这些化合物在虚拟筛选和多级分子对接分析中表现出显著的结合亲和力,超过了对照组厄洛替尼和贝伐珠单抗+利妥昔单抗。此外,这些化合物还具有一流的药物相似性和 ADMET 特性。在 200 ns 分子动力学(MD)模拟和 MM-GBSA 计算过程中,这五种有前途的候选药物还具有很强的与受体结合的能力,并能与受体保持稳定。此外,DFT 分析表明,在所有候选药物中,橙皮素、棉子素和槲皮素最具潜力。我们的研究结果表明,这三种候选药物可以精确地靶向表皮生长因子受体和血管内皮生长因子受体-2,并有可能作为一种单药同时作用于这两种途径。
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Unveiling promising phytocompounds from Moringa oleifera as dual inhibitors of EGFR(T790M/C797S) and VEGFR-2 in non-small cell lung cancer through in silico screening, ADMET, dynamics simulation, and DFT analysis

Non-small cell lung cancer (NSCLC) is among the main causes of mortality from cancer around the globe, affecting all genders. Current treatments mainly focus on tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR). However, resistance mechanisms, such as the emergence of T790M and C797S EGFR mutations and upregulation of VEGFR-2, often hinder the effectiveness of TKIs. Thereby, EGFR and VEGFR-2 present an intriguing opportunity for the treatment of NSCLC by developing dual-acting drugs. This research aims to evaluate prospective Moringa oleifera L. (MO)-originated compounds to efficiently block both of these receptors. In our research, we screened a library of 200 compounds sourced from MO, a plant known for its remarkable therapeutic potential. We identified five intriguing phytocompounds: hesperetin, gossypetin, quercetin, gallocatechin, and epigallocatechin, as potential anti-cancer agents. The compounds have demonstrated notable binding affinity in virtual screening and multi-stage molecular docking analysis, surpassing the controls, Erlotinib and Bevacizumab + Rituximab. In addition, these compounds demonstrate top-notch drug-likeness and ADMET properties. The five promising drug candidates also had a strong ability to bind to receptors and stayed stable with them during the 200 ns molecular dynamics (MD) simulation and MM-GBSA calculation. Furthermore, DFT analysis indicates that hesperetin, gossypetin, and quercetagetin stand out as the most promising drug candidates among all others. The findings of our study suggest that these three therapeutic candidates can precisely target both EGFR and VEGFR-2 and can potentially act on both of these pathways as a single agent.

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来源期刊
Journal of Genetic Engineering and Biotechnology
Journal of Genetic Engineering and Biotechnology Biochemistry, Genetics and Molecular Biology-Biotechnology
CiteScore
5.70
自引率
5.70%
发文量
159
审稿时长
16 weeks
期刊介绍: Journal of genetic engineering and biotechnology is devoted to rapid publication of full-length research papers that leads to significant contribution in advancing knowledge in genetic engineering and biotechnology and provide novel perspectives in this research area. JGEB includes all major themes related to genetic engineering and recombinant DNA. The area of interest of JGEB includes but not restricted to: •Plant genetics •Animal genetics •Bacterial enzymes •Agricultural Biotechnology, •Biochemistry, •Biophysics, •Bioinformatics, •Environmental Biotechnology, •Industrial Biotechnology, •Microbial biotechnology, •Medical Biotechnology, •Bioenergy, Biosafety, •Biosecurity, •Bioethics, •GMOS, •Genomic, •Proteomic JGEB accepts
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