Phytochemical Profiling and Structure-Based Computational Characterization of Marrubium vulgare L. Compounds as Hsp90...

Marrubium vulgare L. is a medicinal plant widely used in traditional medicine, with emerging evidence of anticancer potential. This study investigated its bioactive compounds as inhibitors of Heat Shock Protein 90 alpha (Hsp90α), a molecular chaperone essential for oncogenic protein stability. Organic and aqueous extracts were profiled using high-performance liquid chromatography-mass spectrometry (HPLC-MS), revealing a diverse phytochemical composition. Identified compounds were screened against the full-length crystal structure of Hsp90α using a structure-based computational workflow that included extra-precision and domain-specific molecular docking, molecular dynamics (MD) simulations, and MM/GBSA binding free energy calculations. Pharmacokinetic and toxicity profiles were evaluated through ADMET predictions. This study elucidated the chemical composition of the plant and identified two hit compounds: Forsythoside B bound preferentially to the middle domain, potentially interfering with client protein interactions, and chlorogenic acid targeted the C-terminal domain, which regulates dimerization and allosteric activity. Both ligands displayed stable protein-ligand interactions during MD and favorable ADMET properties. These findings provide the first integrated chemical and computational prediction framework, suggesting that some M. vulgare metabolites may interact with Hsp90, highlighting its potential as a source of novel anticancer scaffolds and laying the groundwork for experimental validation and drug development.