Research Paper Volume 13, Issue 6 pp 8248—8275

Transcriptome profiling reveals target in primary myelofibrosis together with structural biology study on novel natural inhibitors regarding JAK2

Weihang Li1, *, , Bin Yuan1,6, *, , Yingjing Zhao4, , Tianxing Lu5, , Shilei Zhang1, , Ziyi Ding1, , Dong Wang1, , Sheng Zhong3, , Guangxun Gao2, , Ming Yan1, ,

  • 1 Department of Orthopaedics, Xijing Hospital, The Fourth Military Medical University, Xi’an, China
  • 2 Department of Hematology, Xijing Hospital, The Fourth Military Medical University, Xi’an, China
  • 3 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
  • 4 College of Clinical Medicine, Jilin University, Changchun, China
  • 5 Hou Zonglian Medical Experimental Class, Xi'an Jiaotong University, Xi'an, Shaanxi, China
  • 6 Department of Orthopaedics, Daxing Hospital, Xi’an, China
* Co-first authors

Received: June 22, 2020       Accepted: December 18, 2020       Published: March 3, 2021
How to Cite

Copyright: © 2021 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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.


ADMET: Absorption, Distribution, Metabolism, Excretion, Toxicity; BBB: Blood-brain barrier; CYP2D6: Cytochrome P4502D6; DAVID: Database for annotation, visualization, and integrated discovery; DS: Discovery Studio; DTP: Developmental toxicity potential; GO: Gene Ontology; GSEA: Gene set enrichment analysis; JAK2: Janus Kinase 2; KEGG: Kyoto Encyclopedia of Genes and Genomes; LD50: Lethal Dose, 50%; LOAEL: Lowest observed adverse effect level; PMF: Primary Myelofibrosis; PPB: Plasma protein binding; PPI: Protein-protein interaction; RMSD: Root mean squared deviation; STRING: Search tool for retrieval of interacting genes.