Department of Orthopaedics, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
Department of Orthopaedics, Daxing Hospital, Xi'an, China.
Aging (Albany NY). 2021 Mar 3;13(6):8248-8275. doi: 10.18632/aging.202635.
This study aimed to identify effective targets for carcinogenesis of primary myelofibrosis (PMF), as well as to screen ideal lead compounds with potential inhibition effect on Janus kinase 2 to contribute to the medication design and development. Gene expression profiles of GSE26049, GSE53482, GSE61629 were obtained from the Gene Expression Omnibus database. The differentially expressed genes were identified, and functional enrichment analyses such as Gene Ontology, protein-protein interaction network etc., were performed step by step. Subsequently, highly-precise computational techniques were conducted to identify potential inhibitors of JAK2. A series of structural biology methods including virtual screening, ADMET (absorption, distribution, metabolism, excretion, and toxicity) prediction, molecule docking, molecular dynamics simulation etc., were implemented to discover novel natural compounds. Results elucidated that PMF patients had abnormal LCN2, JAK2, MMP8, CAMP, DEFA4, LTF, MPO, HBD, STAT4, EBF1 mRNA expression compared to normal patients. Functional enrichment analysis revealed that these genes were mainly enriched in erythrocyte differentiation, neutrophil degranulation and killing cells of other organisms. Two novel natural compounds, ZINC000013513540 and ZINC000004099068 were found binding to JAK2 with favorable interaction energy together with high binding affinity. They were predicted with non-Ames mutagenicity, low-rodent carcinogenicity, less developmental toxicity potential as well as non-toxicity with liver. Molecular dynamics simulation demonstrated that these two complexes: ZINC000013513540-JAK2 and ZINC000004099068-JAK2 could exist stably under natural circumstances. In conclusion, this study revealed hub genes in the carcinogenesis of PMF. ZINC000013513540 and ZINC000004099068 were promising drugs in dealing with PMF. This study may also accelerate exploration of new drugs.
本研究旨在确定原发性骨髓纤维化（PMF）发生癌变的有效靶点，并筛选出具有潜在抑制 Janus 激酶 2 作用的理想先导化合物，为药物设计和开发提供参考。从基因表达综合数据库中获取 GSE26049、GSE53482、GSE61629 三个数据集的基因表达谱数据。识别差异表达基因，并逐步进行基因本体论、蛋白质-蛋白质相互作用网络等功能富集分析。随后，采用高精度计算技术识别 JAK2 的潜在抑制剂。采用一系列结构生物学方法，包括虚拟筛选、吸收、分布、代谢、排泄和毒性（ADMET）预测、分子对接、分子动力学模拟等，发现新型天然化合物。结果表明，与正常患者相比，PMF 患者的 LCN2、JAK2、MMP8、CAMP、DEFA4、LTF、MPO、HBD、STAT4、EBF1mRNA 表达异常。功能富集分析表明，这些基因主要富集在红细胞分化、中性粒细胞脱颗粒和杀伤其他生物体的细胞。发现两种新型天然化合物 ZINC000013513540 和 ZINC000004099068 与 JAK2 结合，具有良好的相互作用能和高结合亲和力。预测它们具有非致突变性、低啮齿动物致癌性、较少的发育毒性潜力以及对肝脏无毒。分子动力学模拟表明，这两种复合物：ZINC000013513540-JAK2 和 ZINC000004099068-JAK2 可以在自然条件下稳定存在。总之，本研究揭示了 PMF 癌变过程中的枢纽基因。ZINC000013513540 和 ZINC000004099068 是治疗 PMF 的有前途的药物。本研究也可能加速新药的探索。
