Design, Molecular Docking, and Molecular Dynamics Simulation of Cyclohexanone Curcumin Derivatives as Anti-Breast Cancer Agents

Human epidermal growth factor receptor-2 (HER2) is a critical therapeutic target in oncology, yet developing effective inhibitors remains a priority. While curcumin derivatives have emerged as potential anticancer agents, their specific molecular interactions with HER2 require further elucidation. This study investigated the inhibitory potential of twelve curcumin derivatives against HER2 using an integrated in silico strategy that comprised molecular docking, 100 ns molecular dynamics (MD) simulations, Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) free energy calculations, and Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiling. Docking analyses revealed that compounds I (2,6-bis((E)-4-methoxy-3-nitrobenzylidene)cyclohexan-1-one), K (2,6-bis((E)-4-chloro-3-nitrobenzylidene) cyclohexan-1-one), A (2,6-bis((E)-3-hydroxy-4-methoxybenzylidene)cyclohexan-1-one), and C (2,6-bis((E)-4-chloro-3-hydroxybenzylidene)cyclohexan-1-one) exhibited significantly stronger binding affinities (−11.04 to −10.05 kcal/mol) than the native ligand 03Q (−8.89 kcal/mol), forming stable interactions with key active-site residues, particularly Met801. MD simulations and MM-PBSA calculations validated the conformational stability of these complexes, with Compound I demonstrating the most favorable binding free energy (−45.39 kcal/mol). Although all derivatives complied with Lipinski’s Rule of Five, ADMET predictions highlighted distinct safety profiles. Compounds A and C displayed superior pharmacokinetics, high intestinal absorption, and no mutagenicity or hepatotoxicity. Conversely, the high-affinity compounds I and K exhibited potential toxicity liabilities despite their dynamic stability. Collectively, these findings identify Compound A as the most promising lead candidate for HER2-targeted drug development, while the potent scaffold of Compound I warrants structural optimization to improve its safety profile.