Mechanism of action of Salvia miltiorrhiza on avascular necrosis of the femoral head determined by integrated network pharmacology and molecular dynamics simulation.

Avascular necrosis of the femoral head (ANFH) is a progressive, multifactorial, and challenging clinical condition that often leads to hip dysfunction and deterioration. The pathogenesis of ANFH is complex, and there is no foolproof treatment strategy. Although some pharmacologic and surgical treatments have been shown to improve ANFH, the associated side effects and poor prognosis are of concern. Therefore, there is an urgent need to explore therapeutic interventions with superior efficacy and safety to improve the quality of life of patients with ANFH. Salvia miltiorrhiza (SM), a traditional Chinese medicine with a long history, is widely used for the treatment of cardiovascular and musculoskeletal diseases due to its multiple pharmacological activities. However, the molecular mechanism of SM for the treatment of ANFH is still unclear. Therefore, this study aimed to explore the potential targets and mechanisms of SM for the treatment of ANFH using network pharmacology and molecular modeling techniques. By searching multiple databases, we screened 52 compounds and 42 common targets involved in ANFH therapy and identified dan-shexinkum d, cryptotanshinone, tanshinone iia, and dihydrotanshinlactone as key compounds. Based on the protein-protein interaction (PPI) network, TP53, AKT1, EGFR, STAT3, BCL2, IL6, and TNF were identified as core targets. Subsequent enrichment analysis revealed that these targets were mainly enriched in the AGE-RAGE, IL-17, and TNF pathways, which were mainly associated with inflammatory responses, apoptosis, and oxidative stress. In addition, molecular docking and 100 nanoseconds molecular dynamics (MD) simulations showed that the bioactive compounds of SM had excellent affinity and binding strength to the core targets. Among them, dan-shexinkum d possessed the lowest binding free energy (-215.874 kcal/mol and - 140.277 kcal/mol, respectively) for AKT1 and EGFR. These results demonstrated the multi-component, multi-target, and multi-pathway intervention mechanism of SM in the treatment of ANFH, which provided theoretical basis and clues for further experimental validation and development of anti-ANFH drugs.