Structural characterization and in silico evaluation of bioactive compounds from Rhus cotinus (Syn. Cotinus coggygria) roots as potential EGFR inhibitors for brain Cancer

Abstract

Brain cancer, particularly glioblastoma, represents a significant therapeutic challenge due to its aggressive nature and limited treatment options. The epidermal growth factor receptor (EGFR) has emerged as a crucial target for brain cancer therapy, as its irregular activation drives tumor growth, proliferation, and invasion. In this study, we explored the potential of bioactive compounds from the roots of Rhus cotinus (Syn. Cotinus coggygria) as EGFR inhibitors for brain cancer treatment. Through comprehensive phytochemical studies, nine compounds were isolated and characterized, including β-sitosterol, lupeol, oleanolic acid, apigenin, kaempferol, quercetin, di-galloyl, 1,2-di-O-galloyl-β-d-glucopyranosyl, and Quercetin-3-O-arabinogalactoside. Molecular docking studies were employed to investigate the binding interactions and ADMET profile of these compounds with the EGFR kinase domain. Notably, the natural compounds exhibited binding modes analogous to clinically approved EGFR inhibitors, engaging crucial residues such as Met769, Leu820, and Asp831 through hydrogen bonding and hydrophobic interactions. The docking scores of the compounds ranges from −9.0 to −7.4 kcal/mol with lupeol being the most active and Quercetin-3-O-arabinogalactoside being the least active. The ADME-Tox analysis of the compounds revealed favorable pharmacokinetic profiles and compliance with drug-likeness criteria for most compounds; selected compounds demonstrated good bioavailability and BBB permeability, while toxicity predictions highlighted risks such as hepatotoxicity, neurotoxicity, and immunotoxicity, thus providing a foundation for optimizing safety and therapeutic potential. These findings suggest the potential of R. cotinus root-derived compounds to modulate EGFR activity and inhibit its oncogenic signaling in brain cancer cells. While further experimental validation is necessary, this study highlights the therapeutic potential of natural products from R. cotinus roots as a valuable source of lead compounds for the development of novel EGFR-targeted therapies against glioblastoma multiforme.