Azmi Muhammad Bilal, Nasir Mushyeda Fatima, Asif Uzma, Kazi Mohsin, Uddin Mohammad N, Qureshi Shamim Akhtar
Computational Biochemistry Research Laboratory, Department of Biochemistry, Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan.
Department of Biosciences, Faculty of Life Sciences, Mohammad Ali Jinnah University, Karachi, Pakistan.
Front Mol Biosci. 2024 Apr 22;11:1384214. doi: 10.3389/fmolb.2024.1384214. eCollection 2024.
Intrauterine growth restriction (IUGR) and preeclampsia (PE) are intricately linked with specific maternal health conditions, exhibit shared placental abnormalities, and play pivotal roles in precipitating preterm birth (PTB) incidences. However, the molecular mechanism underlying the association between PE and IUGR has not been determined. Therefore, we aimed to analyze the data of females with PE and those with PE + IUGR to identify the key gene(s), their molecular pathways, and potential therapeutic interactions.
In this study, a comprehensive relationship analysis of both PE and PE + IUGR was conducted using RNA sequence datasets. Using two datasets (GSE148241 and GSE114691), differential gene expression analysis via DESeq2 through R-programming was performed. Gene set enrichment analysis was performed using ClusterProfiler, protein‒protein interaction (PPI) networks were constructed, and cluster analyses were conducted using String and MCODE in Cytoscape. Functional enrichment analyses of the resulting subnetworks were performed using ClueGO software. The hub genes were identified under both conditions using the CytoHubba method. Finally, the most common hub protein was docked against a library of bioactive flavonoids and PTB drugs using the PyRx AutoDock tool, followed by molecular dynamic (MD) simulation analysis. Pharmacokinetic analysis was performed to determine the ADMET properties of the compounds using pkCSM.
We identified eight hub genes highly expressed in the case of PE, namely, PTGS2, ENG, KIT, MME, CGA, GAPDH, GPX3, and P4HA1, and the network of the PE + IUGR gene set demonstrated that nine hub genes were overexpressed, namely, PTGS2, FGF7, FGF10, IL10, SPP1, MPO, THBS1, CYBB, and PF4. PTGS2 was the most common hub gene found under both conditions (PE and PEIUGR). Moreover, the greater (-9.1 kcal/mol) molecular binding of flavoxate to PTGS2 was found to have satisfactory pharmacokinetic properties compared with those of other compounds. The flavoxate-bound PTGS2 protein complex remained stable throughout the simulation; with a ligand fit to protein, , a RMSD ranging from ∼2.0 to 4.0 Å and a RMSF ranging from ∼0.5 to 2.9 Å, was observed throughout the 100 ns analysis.
The findings of this study may be useful for treating PE and IUGR in the management of PTB.
胎儿生长受限（IUGR）和子痫前期（PE）与特定的孕产妇健康状况密切相关，表现出共同的胎盘异常，并且在早产（PTB）发生率的增加中起关键作用。然而，PE与IUGR之间关联的分子机制尚未确定。因此，我们旨在分析患有PE和患有PE + IUGR的女性的数据，以确定关键基因、它们的分子途径以及潜在的治疗相互作用。
在本研究中，使用RNA序列数据集对PE和PE + IUGR进行了全面的关系分析。使用两个数据集（GSE148241和GSE114691），通过R编程中的DESeq2进行差异基因表达分析。使用ClusterProfiler进行基因集富集分析，构建蛋白质-蛋白质相互作用（PPI）网络，并使用Cytoscape中的String和MCODE进行聚类分析。使用ClueGO软件对所得子网进行功能富集分析。使用CytoHubba方法在两种条件下鉴定枢纽基因。最后，使用PyRx AutoDock工具将最常见的枢纽蛋白与生物活性黄酮类化合物和PTB药物库进行对接，随后进行分子动力学（MD）模拟分析。使用pkCSM进行药代动力学分析以确定化合物的ADMET特性。
我们鉴定出在PE病例中高表达的8个枢纽基因，即PTGS2、ENG、KIT、MME、CGA、GAPDH、GPX3和P4HA1，并且PE + IUGR基因集的网络表明有9个枢纽基因过表达，即PTGS2、FGF7、FGF10、IL10、SPP1、MPO、THBS1、CYBB和PF4。PTGS2是在两种条件下（PE和PEIUGR）发现的最常见的枢纽基因。此外，发现黄酮哌酯与PTGS2的分子结合力更强（-9.1 kcal/mol），与其他化合物相比具有令人满意的药代动力学特性。在整个模拟过程中，黄酮哌酯结合的PTGS2蛋白复合物保持稳定；在整个100 ns分析中，观察到配体与蛋白质的拟合情况，RMSD范围约为2.0至4.0 Å，RMSF范围约为0.5至2.9 Å。
本研究的结果可能有助于在PTB的管理中治疗PE和IUGR。
