Network pharmacology- and molecular docking-based approach for predicting key targets and the potential mechanism of Tripterygium wilfordii Hook F for the treatment of acute lymphoblastic leukaemia

Abstract

ABSTRACT This study explored the main active ingredients and the underlying mechanism of TwHF in the treatment of ALL by network pharmacology and molecular docking. TCMSP, OMIM and GeneCards databases were used to obtain active ingredients of TwHF to predict related targets of TwHF and ALL. Cytoscape and STRING databases were used to construct Ingredient-target-disease and PPI networks, respectively. Enrichment analysis of GO and KEGG was conducted by Bioconductor database. Molecular docking was performed using the Autodock platform to predict the binding of the active components to key action targets.CCK-8 assay was performed to measure the effects of drugs on the proliferation of ALL cells. The ingredient-target-disease network contained 16 compounds and 43 corresponding targets. Key targets included VEGFA, CASP3, RELA, ESR1, BCL2, and MAPK8. There were 79 GO items in the GO enrichment analysis (p < .05) and 91 signalling pathways (p < .05) in KEGG primarily including tumour necrosis factor signalling pathway and apoptosis pathway. Molecular docking results showed that triptolide, kaempferol and other phytocompounds had a high affinity for the corresponding targets.CCK-8 assay suggested that triptolide and kaempferol have anti-proliferative effects on ALL cells. Triptolide, kaempferol and other active ingredients from TwHF may exert therapeutic effects on ALL through multiple pathways and targets. Highlights There are 43 potential action targets of TwHF for ALL treatments, among which VEGFA and CASP3 are the core genes. 16 active ingredients including triptolide and kaempferol play a role in the treatment of leukaemia. The bioactive components of TwHF can treat the ALL by modulating biological processes such as nuclear receptor activity and biological pathways such as apoptosis pathway and tumour necrosis factor signalling pathway. Triptolide and kaempferol significantly inhibited the viability of Jurkat, MOLT-4 and Nalm-6 cells in a concentration- and time-dependent manner. ALL, Acute lymphoblastic leukaemia; BCL2, B lymphocyte tumor-2 gene; CASP3, Caspase-3; CCK-8, cell counting kit 8; DL, Drug-likeness; ESR1, estrogen receptor 1; MAPK8, mitogen-activated protein kinase 8; OB, Oral bioavailability; OD, optical density; PPI, protein–protein interaction; PDGF, platelet-derived growth factor; SD, standard deviation; TwHF, Tripterygium wilfordii Hook F; Triptolide: Kaempferol; TCMSP, Traditional Chinese Medicine Systems Pharmacology; T-ALL, T-cell Acute lymphoblastic leukaemia; TRAIL, Tumor necrosis factor-related apoptosis-inducing ligand; TPL, Triptolide; VEGFA, vascular endothelial growth factor A gene.