Unlocking the Anticancer Potential of Metal-Curcumin Complexes: Docking Insights with EGFR

Abstract

The Epidermal Growth Factor Receptor (EGFR) plays a pivotal role in cervical cancer progression by driving uncontrolled cell proliferation and survival. Given its oncogenic significance, EGFR remains a prime therapeutic target for cancer drug development. Curcumin, a bioactive polyphenol, exhibits promising anticancer properties but suffers from poor solubility and bioavailability, limiting its clinical application. To enhance its pharmacological potential, metal complexation has been explored as a strategy to improve its pharmacokinetics and bioactivity. This study employed molecular docking to assess the binding affinities of curcumin and its metal complexes (Ca, Cu, Mg, Na, Zn) with two EGFR conformations: the active kinase domain (PDB ID: 1M17) and the extracellular ligand-binding domain (PDB ID: 4ZSE). Docking analyses revealed that Ca-Bicurcumin (-11.1 kcal/mol), Na-Bicurcumin (-11.0 kcal/mol), and Cu, Mg, and Zn-Bicurcumin complexes (-10.8 kcal/mol each) exhibited strong binding affinities toward 1M17, outperforming the reference ligand AQ4 (-7.0 kcal/mol) and native curcumin (-7.3 kcal/mol). Similarly, Cu-Bicurcumin (-11.0 kcal/mol), along with Ca, Mg, and Na-Bicurcumin complexes (-10.9 kcal/mol each), displayed superior interactions with 4ZSE, exceeding the binding of ANP (-9.4 kcal/mol) and curcumin (-7.2 kcal/mol). These enhanced interactions resulted from strong hydrogen bonding, hydrophobic interactions, and electrostatic forces, improving receptor complementarity. The findings suggest that metal-curcumin complexes hold promise as EGFR-targeted therapeutics, potentially overcoming curcumin’s pharmacokinetic limitations while enhancing its anticancer efficacy. Further, in vitro kinase inhibition assays and in vivo tumor regression studies are necessary to validate their therapeutic potential in EGFR-driven cancers.