Network pharmacology and in silico approaches to uncover multitargeted mechanism of action of Zingiber zerumbet rhizomes for the treatment of idiopathic pulmonary fibrosis

Abstract

Background Idiopathic pulmonary fibrosis (IPF) is a disease with high mortality, and there are only two specific drugs available for therapeutic management with limitations. The study aims to identify comprehensive therapeutic mechanisms of Zingiber zerumbet rhizomes (ZZR) to treat IPF by using network pharmacology followed battery of in silico studies. Methods The protein-protein interaction network was developed using Cytoscape to obtain core disease targets involved in IPF and their interactive molecules of ZZR. Based on the pharmacophore properties of phytomolecules from ZZR, the drug targets in IPF were explored. Protein-protein interaction network was built in Cytoscape to screen potential targets and components of ZZR. Molecular docking and dynamics were conducted as an empirical study to investigate the mechanism explored through network pharmacology in relation to the hub targets. Results The network analysis conferred kaempferol derivatives that had demonstrated a promising therapeutic effect on the perturbed, robust network hubs of TGF-β1, EGFR, TNF-α, MMP2 & MMP9 reported to alter the biological process of mesenchymal transition, myofibroblast proliferation, and cellular matrix deposition in pulmonary fibrosis. The phytomolecules of ZZR act on two major significant pathways, namely the TGF-β-signaling pathway and the FOXO-signaling pathway, to inhibit IPF. Confirmational molecular docking and dynamics simulation studies possessed good stability and interactions of the protein-ligand complexes by RMSD, RMSF, rGyr, SASA, and principal component analysis (PCA). Validated molecular docking and dynamics simulations provided new insight into exploring the mechanism and multi-target effect of ZZR to treat pulmonary fibrosis by restoring the alveolar phenotype through cellular networking. Conclusions Network pharmacology and in silico studies confirm the multitargeted activity of ZZR in the treatment of IPF. Further in vitro and in vivo studies are to be conducted to validate these findings.