Mol Divers. 2026 Jun 4. doi: 10.1007/s11030-026-11602-6. Online ahead of print.
ABSTRACT
Angiotensin II (AngII)-mediated oxidative stress is a primary driver of vascular endothelial dysfunction, a critical pathogenesis in hypertension and cardiovascular diseases. While baicalin is recognized for its cardioprotective properties, the precise atomic-level mechanism governing its interaction with the Nrf2 signaling axis remains to be fully characterized. This study employs an integrated in silico and in vitro framework to elucidate the molecular determinants by which baicalin mitigates AngII-induced endothelial injury. Quantum chemical calculations using Density Functional Theory (DFT) revealed a relatively narrow HOMO-LUMO energy gap (∆E = 3.86 eV), suggesting enhanced electronic reactivity and a potential tendency toward redox-related activity. Pharmacokinetic profiling further predicted a favorable ADMET profile with negligible toxicity risks. Molecular docking and 500 ns molecular dynamics (MD) simulations identified a stable, high-affinity binding mode (∆Gbind=-34.54 kcal/mol) for baicalin within the key regulatory pocket. Notably, Free Energy Landscape (FEL) and per-residue energy decomposition analyses unveiled a synergistic binding mechanism, driven predominantly by a persistent backbone hydrogen bond at Val608 and hydrophobic clustering involving Val369 and Cys368. Experimental validation in AngII-stimulated HUVECs corroborated these computational predictions, demonstrating that baicalin treatment effectively abrogates the pathological upregulation of Keap1, thereby facilitating Nrf2 stabilization and the subsequent restoration of downstream cytoprotective enzymes (HO-1 and NQO-1). Taken together, these findings provide a structural elucidation of the mechanism by which baicalin activates the Nrf2 signaling pathway through direct binding to Keap1 and the subsequent inhibition of Nrf2 ubiquitination and degradation. Consequently, this study establishes a theoretical and experimental foundation for its therapeutic application in vascular protection.
PMID:42240758 | DOI:10.1007/s11030-026-11602-6