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

<i>Marrubium vulgare</i> 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 <i>M. vulgare</i> 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.