Therapeutic targets and molecular mechanism of calycosin for the treatment of cerebral ischemia/reperfusion injury

Abstract

This study was designed to understand the pivotal anti-cerebral ischemia/reperfusion injury (CIRI) targets and pathways of calycosin through network pharmacology and molecular docking analyses. In this study, bioinformatics tools were employed to characterize and identify the pharmacological functions and mechanisms of calycosin for CIRI management. The network pharmacology data identified potential, merged CIRI-associated targets of calycosin including tumor protein p53 (TP53), protein kinase B (AKT1), vascular endothelial growth factor A (VEGFA), interleukin 6, tumor necrosis factor (TNF), and mitogen-activated protein kinase 1 (MAPK1). Molecular docking analysis indicated the binding efficacy of calycosin with three of the targets, namely TP53, AKT1, and VEGFA. The biological processes of calycosin for the treatment of CIRI are mainly involved in the improvement of endothelial cell proliferation and growth, inflammatory development, and cellular metabolism. In addition, the anti-CIRI actions of calycosin were primarily through suppression of the toll-like receptor, PI3K-AKT, TNF, MAPK, and VEGF signaling pathways. Taken together, the current bioinformatic findings revealed pivotal targets, biological functions, and pharmacological mechanisms of calycosin for the treatment of CIRI. In conclusion, calycosin, a functional phytoestrogen, can be potentially used for the treatment of CIRI in future clinical trials.

Keywords: bioinformatics; biotargets; calycosin; cerebral ischemia/reperfusion injury; network pharmacology.

Figure 1

Flowchart of the current bioinformatics tools used for this study to reveal the pivotal targets and molecular mechanisms underlying the anti-CIRI action of calycosin through network pharmacology and molecular docking methods.

Figure 2

Venn diagram showing all the common, merged targets of calycosin and CIRI. All merged targets are interrelated in the network diagram.

Figure 3

Subnetwork clusters of identified targets for calycosin against CIRI obtained using MCODE algorithm.

Figure 4

CIRI-related pivotal targets of calycosin. Six pivotal targets were screened and identified from merged targets, namely TP53, AKT1, VEGFA, IL6, TNF, and MAPK1.

Figure 5

Top 20 pharmacological processes and molecular pathways of calycosin for CIRI management. Based on enrichment analysis, both pharmacological processes and molecular pathways were revealed to understand the mechanism of action of calycosin for the treatment of CIRI.

Figure 6

Docking poses of calycosin on three identified targets. By using molecular docking analysis, the data demonstrated that effective binding capacities of calycosin with CIRI were identified in (A) TP53 (2MWO), (B) AKT1 (3O96), and (C) VEGFA (5T89) targets.