Investigating the molecular mechanism of iguratimod act on SLE using network pharmacology and molecular docking analysis

Abstract

Objective: Iguratimod (IGU) is a novel small disease-modifying compound widely used in Asia for the treatment of rheumatic diseases. IGU is a methane sulfonanilide. We applied network pharmacology to investigate the pharmacological mechanisms of IGU act on SLE. Methods: We used PharmMapper, UniProt, and OMIM databases to screen the potential targets of IGU, and the SLE-related disease targets were predicted. Hub target genes among the intersections of the potential targets (IGU) and related genes (SLE) were validated using the PPI network generated by the String database. GO and KEGG enrichment analyses were carried out using the David online platform. Finally, the molecular docking of hub targets and their corresponding compounds were completed through AutoDock Vina and PyMOL software for visualization. Result: A total of 292 potential targets of IGU, 6501 related disease targets of SLE, and 114 cross targets were screened from the aforementioned database. Network topology analysis identified 10 hub targets, such as CASP3, AKT1, EGFR, MMP9, and IGF1. GO enrichment analysis mainly focuses on the negative regulation of the apoptotic process and signal transduction. KEGG enrichment analysis illustrated that the PI3K-AKT signaling pathway, MAPK signaling pathway, and FoxO signaling pathway might play a significant role in the pharmacological mechanisms of IGU act on SLE. Molecular docking confirmed that the IGU ligand had strong binding activity to the hub targets. Conclusion: This study based on network pharmacology and molecular docking validation preliminarily revealed the protein targets affected by IGU acting on SLE through, and explored potential therapeutic mechanism role of IGU in SLE treatment by multi pathways.

Keywords: iguratimod; molecular docking; network pharmacology; systemic lupus erythematosus; treatment.

FIGURE 1

Study flow.

FIGURE 2

Associated targets predicted from databases involved in IGU (Ligand: 124246) and SLE. (A) 3D chemical structures of IGU. (B) 2D chemical structures of IGU. (C) Venn diagram of IGU targets and SLE.

FIGURE 3

Bioinformatics analysis of overlapping targets. (A) Protein–protein interaction (PPI) network (B) Top 10 hub genes in the PPI network. (C) IGU-PACS potential target network. (D) Bar chart of GO enrichment analysis of the hub target of IGU in the treatment of SLE (the top 10 items); (green) biological processes, (orange) cell components, and (purple) molecular functions. (E) Bubble chart of KEGG analysis of the hub target of IGU in the treatment of SLE (the top 20 items). (F) Network of KEGG (the top 20 items) signaling pathway genes; (blue) pathway, (green) IGU, (yellow) four hub genes relevant to pathways and SLE, and (purple) potential target.

FIGURE 4

Pictures of KEGG gene pathway is displayed. (A) FoxO signaling pathway; (yellow node) genes existing in this IGU and SLE network. (B) PI3K/AKT signaling pathway; (purple edge) road map of genes associated with our network. (C) The MAPK signaling pathway; (purple edge) road map of genes associated with our network. (D) Chemokine signaling pathway; (purple edge) road map of genes associated with our network.

FIGURE 5

Diagrams of docking models of IGU and the four most related target molecules. 5–1. (A–D) Docking views of target proteins CASP3, AKT1, EGFR, and IGF1 with IGU, respectively. 5–2. 1, 2, 3, and 4 in each line indicates the description of the following, respectively: 1) Number 1 of each group is a cartoon comparison plot of the binding of IGU, inhibitor, and the target protein, with IGU as a yellow structure, and the four groups of inhibitors colored green, light blue, white, and orange, respectively. 2) Number 2 of each group is a surface modeling of number 2, respectively. 3) Number 3 of each group is a concrete picture of the binding of IGU to the target protein, respectively. 4) Number 4 of each group is a concrete picture of inhibitor binding to the target protein, respectively. (A) CASP3-IGU. (B) AKT1-IGU. (C) EGFR-IGU. (D) IGF1-IGU.