Genistein potential and mechanisms against diabetes osteoporosis: An integrated study of network pharmacology, molecular docking, and molecular dynamics simulation

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Introduction Diabetes mellitus (DM) and osteoporosis (OP) are common chronic diseases worldwide with complex pathological interlinked relationship. Due to persistent hyperglycemia, insulin resistance and accumulation of advanced glycation end products (AGEs) in diabetic patients accompanied by chronic low-grade inflammation and oxidative stress, the balance of bone remodeling gets disrupted. Genistein (GN) is an isoflavone present in soy known to have multiple molecular effects making it a promising candidate for Diabetic Osteoporosis (DO) therapy. Methods In this study we systematically evaluated the ADME profile and toxicity prediction of GN using SwissADME and ProTox-II.DO targets and GN treatment targets were obtained from public databases via Network Pharmacology (NP) analysis. Protein–protein interaction (PPI) networks were constructed to screen out the hub genes using the STRING database and Cytoscape software. Cluster analysis of the protein modules were then performed using the Cytoscape MCODE plugin. Furthermore Gene Ontology enrichment (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed using the DAVID database. Finally molecular docking (MD) using AMDock for binding affinity and molecular dynamic simulations (MS)studies, including MM/GBSA were performed using Schrodinger to validate the stability and flexibility. In vivo validation was subsequently employed to elucidate the therapeutic mechanisms of GN against DO. Results Key findings revealed GN as a safe and effective drug in the treatment of DO. Five hub genes—EGFR, ESR1, PTGS2, MMP9 and PPARG—were identified showing strong binding affinity with GN. These proteins were found to be responsible for the maximum number of pathway modulations in DO identified by NP and MS. Further,MS confirmed the stability of complexes: 6MS7 and 4PP6 as the best fit within the active binding sites of target drug. Finally, animal experiments confirmed GN as alternative therapy for treating DO. Discussion Overall these findings suggest that GN may exert its beneficial effects in DO by modulating multitargets and multichannel. This study also provides theoretical support for further research and applications of GN. Nevertheless additional molecular expressions studies are more beneficial to validate these mechanisms. Conclusion Our study demonstrated GN-mediated treatment of DO was a complex process involving multiple compounds, targets and pathways related to inhibition of inflammation, promotion of apoptosis, modulation of steroidal hormone receptors and regulation of various metabolic pathways. Overall, this study will enhance the understanding and reveal the potential molecular mechanism of GN in DO therapy.

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