Discovery of anti-glioblastoma natural products based on andrographolide derivatives: efficiently identifying potential multi-target and multifunctional molecules through the integration of in silico methods and experimental verification.

Glioblastoma (GBM) may cause neurological dysfunction, leading to significant physical and mental distress and complicating oncological treatment as well as clinical care. Agents that combine anti-GBM and neuroprotective activities may offer a promising solution to this challenge. Andrographolide exhibits broad-spectrum anti-tumor effects, blood-brain barrier (BBB) permeability, and neuroprotective properties, making it a promising candidate for GBM treatment, though its nephrotoxicity warrants caution. Many andrographolide derivatives with enhanced therapeutic efficacy and reduced nephrotoxicity have been reported. Therefore, this study developed validated pharmacophore models using these andrographolide derivatives to identify natural products with dual anti-GBM and neuroprotective effects, and employed network pharmacology and molecular dynamics (MD) simulations to explore their potential mechanisms of action. Mevastatin was identified as a promising hit compound, exhibiting low cytotoxicity in HK-2 cells while persistently inhibiting A172 cell growth and migration (IC50 = 4.639 µM). It also demonstrates BBB penetrability and potential neuroprotective effects. Network pharmacology analysis revealed that beyond HMGCR, mevastatin may directly interact with 12 additional targets relevant to GBM treatment. MD simulations elucidated its binding mechanisms to MAPK1, MDM2, MMP2, and GRB2. In summary, starting from a series of multi-target and multifunctional natural product derivatives sharing the same core scaffold, this study identified a small molecule that exhibits higher efficacy, lower toxicity, and potential multifunctional activity compared to the reference compound, thus proposing a novel strategy for the discovery of multi-target, multifunctional therapeutic agents.