Computational Modeling of Network Topology and Molecular Dynamics for the Assessment of Therapeutic Potential of the Astragalus Membranaceus-Salvia Miltiorrhiza Drug Pair in the Treatment of Chronic Kidney and Heart Failure.

Abstract

Introduction: The bioactive components of Astragalus membranaceus and Salvia miltiorrhiza improved cardiac and renal function in chronic heart failure (CHF) and chronic kidney disease (CKD), respectively. However, the common regulating molecular mechanisms remain unclear. The aim of this study was to investigate these mechanisms using bioinformatics, network topology, and molecular dynamics simulation techniques.

Methods: The active components and target sites of A. membranaceus and S. miltiorrhiza were obtained from the Traditional Chinese Medicine Systems Pharmacology database. The targets of CKD and CHF were obtained from various databases for a protein-protein interaction analysis. The Gene Ontology (GO) function and Kyotoencyclopedia of genes and genomes (KEGG) pathway enrichment of intersection targets were analyzed by using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) database. Molecular docking and dynamic simulations were conducted on the core ingredients and targets. The diagnostic efficiency of the key targets was evaluated by using receiver-operating characteristic (ROC) curves.

Results: A total of 70 active ingredients and 158 common targets were found. The top five core targets were AKT1, STAT3, TP53, MAPK1, and RELA. The GO enrichment analysis included apoptosis and oxidative stress. The KEGG pathway enrichment results indicated that the drug pair regulated the AGE-receptor for AGE signaling pathway, fluid shear stress and atherosclerosis, and the IL-17 signaling pathway. Molecular docking and dynamic simulations confirmed that the core ingredients had good affinity and stability with the key targets. The ROC curves confirmed the accuracy of every key target for identifying CKD and CHF and demonstrated that combining them improves diagnosis.

Conclusion: The combination of A. membranaceus and S. miltiorrhiza proved effective for the treatment of CKD and CHF through various components, targets, and mechanisms. Moreover, it may predict the diagnostic value of key targets, providing a reference for clinical diagnostic applications.