Objective To investigate the core active components, key targets, and regulatory mechanisms of Zhuling decoction in the intervention of diabetic kidney disease (DKD) using network pharmacology, molecular docking, and molecular dynamics simulation.

Methods Active components and corresponding targets of Zhuling decoction were screened using the TCMSP, BATMAN-TCM 2.0, and Swiss Target Prediction databases. DKD-related targets were retrieved from the GeneCards, TTD, and DrugBank databases, and then intersected with the targets corresponding to the active components to obtain overlapping targets. A protein-protein interaction (PPI) network and a "component-target" network were constructed to identify key targets and key components. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to identify key pathways. A “key component-key target-key pathway” network was constructed, and the binding affinities between core components and core targets were shown via molecular docking and molecular dynamics simulation.

Results Four core components, including polyporoid C, polyporenic acid C, cerevisterol, polyporusterone E and four core targets, including phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), mechanistic target of rapamycin (mTOR), mitogen-activated protein kinase 1 (MAPK1) and protein kinase C alpha （PRKCA） were identified. Among these, mTOR exhibited the lowest binding energy and the strongest binding affinity with the core components, and molecular docking and molecular dynamics simulation indicated that the complexes were stable. Polyporoid C could target all the core targets, mainly through the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway.

Conclusion Zhuling decoction intervenes in DKD by binding its core components to core targets with moderate structural stability, further regulating the activity of related signaling pathways. Polyporoid C presents obvious multi-target properties, and it exhibits preferable binding performance toward the mTOR target. Subsequent research can be carried out focusing on the cascade regulatory axis of "polyporoid C-core targets - PI3K-Akt signaling pathway".

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