Baicalin executes anticancer property via inhibition of MDM2-p53 interaction: a mechanistic study using in silico...

The tumor suppressor p53 plays a central role in regulating intrinsic apoptosis, and its activity is frequently impaired through overexpression of its negative regulator MDM2. Disrupting the MDM2-p53 interaction is therefore a promising strategy to restore p53 function in cancers retaining wild-type p53. Baicalin, a major flavonoid from Scutellaria baicalensis, is known for diverse pharmacological properties, including anticancer activity, but its potential interaction with MDM2 remains insufficiently explored. In this study, we investigated the possible inhibitory potential of baicalin against MDM2 using an integrated computational and cellular approach. Molecular docking predicted a binding affinity of -7.1 kcal/mol, with baicalin occupying the p53-binding pocket of MDM2, whereas the known inhibitor Nutlin-3 showed a docking-predicted binding energy of -7.5 kcal/mol. Molecular dynamics simulations demonstrated stable accommodation of baicalin within the hydrophobic cleft, maintaining key interactions with residues crucial for p53 recognition. Steered MD simulations and MM/PBSA analysis further supported the stability and favorability of the interaction, with binding free energy consistent with moderate affinity ligands. Although baicalin's predicted affinity is lower than that of classical inhibitors such as Nutlin-3, the stability profile suggests a potential to modulate MDM2-p53 interactions. Gene ontology and protein-interaction network analyses suggested downstream enrichment in p53-associated apoptotic pathways. In vitro assays showed that baicalin inhibited proliferation and induced morphological changes more prominently in MCF-7 cells compared to MDA-MB-231 cells, supporting a possible p53-dependent response. Overall, this study provides computational and preliminary cellular evidence that baicalin may interact with MDM2 and contribute to p53-mediated anticancer activity.