Schaftoside from galgeuntang as a multi-target class I histone deacetylase inhibitor: Integrated molecular docking, dynamics, and systems pharmacology analysis.
Abstract
Histone deacetylases (HDACs) are enzymes that remove acetyl groups from lysine residues of histone proteins, playing a critical role in gene expression regulation. Particularly, Class I HDACs (HDAC1, HDAC2, and HDAC8) are implicated in cancer development and have attracted significant interest as therapeutic targets. However, developing isoform-selective HDAC inhibitors remains challenging. We screened 1625 phytocompounds from the Korean herbal formulation Galgeuntang using the Traditional Chinese Medicine Systems Pharmacology database. After applying drug-likeness filtering, 235 compounds underwent molecular docking against HDAC1, HDAC2, and HDAC8. Schaftoside emerged as the sole candidate engaging all three isoforms, with binding energies of -115.1, -103.8, and -135.5 kcal/mol, respectively. ADMET profiling, quantitative cytotoxicity predictions across multiple cancer cell lines, and in silico gene expression analysis were then performed. One hundred nanosecond molecular dynamics simulations confirmed stable complex formation and PCA-based free energy landscape analysis revealed well-defined conformational minima for each complex. Schaftoside exhibited potent predicted cytotoxicity against hematological and gastrointestinal malignancies (selectivity Index: 8.7-18.6), including the cisplatin-resistant A2780cisR ovarian carcinoma line. In silico transcriptomic profiling predicted downregulation of oncogenic drivers (MYC, STAT3, AKT1) with concurrent upregulation of tumor suppressors (TP53, CDKN1A) and suppression of the HDAC machinery itself. ADMET profiling revealed high aqueous solubility but limited membrane permeability, indicating that structural optimization will be required. Schaftoside therefore constitutes a promising multi-target Class I HDAC inhibitor scaffold, warranting experimental validation through enzymatic assays, histone acetylation analysis, and cell-based cytotoxicity testing.