Department of Bioinformatics, Genetic Engineering and Biotechnology Research Institute (GEBRI), University of Sadat City, Sadat, 32897, Egypt.
Agricultural Genetic Engineering Research Institute (AGERI), Agriculture Research Center (ARC), Giza, Egypt; Bioinformatics Program, School of Biotechnology, Nile University, Giza, Egypt.
Comput Biol Med. 2024 Dec;183:109286. doi: 10.1016/j.compbiomed.2024.109286. Epub 2024 Nov 5.
Recent discoveries have illustrated that Lin28A is an oncogene in various cancers, particularly acute myeloid leukemia (AML). The upregulation of Lin28A can actively contribute to tumorigenesis and migration processes in multiple organs. Hence, the inhibition of Lin28A can be achieved by applying phytochemical herbals and targeting Lin28A protein using a computer-aided drug design (CAAD) approach.
In this study, we comprehensively applied several bioinformatics tools, including gene ontologies, gene enrichment analysis, and protein-protein interactions (PPI), to determine the biological pathways, functional gene ontology, and biological pathway. Furthermore, we investigated a list of phytochemical herbs as a candidate drug by applying a computation technique involving molecular docking, density functional theory (DFT), molecular dynamics simulation (MDs), and pharmacokinetic and physiochemical properties by applying the SwissADME, pkCSM, and Molsoft LLC web-servers.
The Lin28A gene is related to two significant enrichment pathways, including proteoglycans in cancer and the pluripotency of stem cells through interactions with different genes such as MAPK12, MYC, MTOR, and PIK3CA. Interestingly, limonin, 18β Glycyrrhetic Acid, and baicalein have the highest binding energy scores of -8.4, -8.2, and -7.3 kcal/mol, respectively. The DFT study revealed that baicalein has a higher reactivity than limonin and 18β-Glycyrrhetic due to a small energy gap between LUMO and HUMO. Molecular dynamics simulation exhibited that baicalein complex with Lin28A protein is more stable than other complexes during simulation time due to low fluctuation with simulation periods as compared with other complexes, which indicated that baicalein was more fitting to docking and combining in the protein cave because of the largest number of H-bonds available for the docking simulation process. Furthermore, the drug-likeness and ADMET profiles revealed the activity of limonin, baicalein, and 18β-glycyrrhizic Acid, which possess significant inhibiting Lin28A proteins.
This study elucidated that baicalein, 18β-glycyrrhizic, and limonin may be applied as potential candidates for targeting Lin28A as an active oncogene for acute myeloid leukemia.
最近的发现表明，Lin28A 是多种癌症（尤其是急性髓系白血病）的致癌基因。Lin28A 的上调可以积极促进多个器官的肿瘤发生和迁移过程。因此，可以通过应用植物化学药物和使用计算机辅助药物设计 (CAAD) 方法靶向 Lin28A 蛋白来抑制 Lin28A。
在这项研究中，我们综合应用了几种生物信息学工具，包括基因本体论、基因富集分析和蛋白质-蛋白质相互作用 (PPI)，以确定生物途径、功能基因本体论和生物途径。此外，我们通过应用涉及分子对接、密度泛函理论 (DFT)、分子动力学模拟 (MDs) 和通过 SwissADME、pkCSM 和 Molsoft LLC 网络服务器进行的药代动力学和物理化学性质的计算技术，研究了一系列植物化学药物作为候选药物。
Lin28A 基因与两个重要的富集途径有关，包括癌症中的蛋白聚糖和通过与 MAPK12、MYC、MTOR 和 PIK3CA 等不同基因的相互作用的干细胞多能性。有趣的是，柠檬苦素、18β-甘草酸和黄芩素的结合能得分分别为-8.4、-8.2 和-7.3 kcal/mol。DFT 研究表明，黄芩素比柠檬苦素和 18β-甘草酸具有更高的反应性，因为 LUMO 和 HUMO 之间的能量间隙较小。分子动力学模拟表明，在模拟时间内，黄芩素与 Lin28A 蛋白的复合物比其他复合物更稳定，因为与其他复合物相比，波动较小，这表明由于可供对接模拟过程使用的氢键数量最多，黄芩素更适合于在蛋白质洞穴中对接和结合。此外，药物相似性和 ADMET 概况揭示了柠檬苦素、黄芩素和 18β-甘草酸的活性，它们具有显著抑制 Lin28A 蛋白的作用。
本研究表明，黄芩素、18β-甘草酸和柠檬苦素可能被用作靶向 Lin28A 的潜在候选物，Lin28A 是急性髓系白血病的一种活性致癌基因。
