In Silico Evaluation of Annonaceous Acetogenins as Potential HER2 and MELK Inhibitors for Targeted Cancer Therapy

Vollständiger Abstract

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Introduction: Targeted cancer therapy focuses on inhibiting specific molecular pathways that drive tumor growth and survival. In this study, computational methods were employed to identify potential acetogenin- based inhibitors of two key anti-apoptotic proteins, HER2 and MELK. Given their crucial involvement in cancer pathogenesis, HER2 and MELK have emerged as significant molecular targets for the development of effective cancer therapies. Acetogenins, a class of bioactive compounds exclusive to the Annonaceae family, have attracted significant attention for their anticancer properties. Methods: A library of 47 acetogenins derived from Annona muricata and Annona squamosa was screened using molecular docking, and the top-scoring ligand–protein complexes were further evaluated through 100 ns molecular dynamics (MD) simulations. Results: Docking results identified squamocin-C and annocherin as the top-scoring potential binders for HER2 and MELK, respectively, that exhibited predicted binding energies ranging from -171.43 to -133.50 kcal/mol in docking studies and favorable interaction profiles with key active-site residues. MD simulations revealed that the annocherin–MELK complex maintained greater structural stability and lower root mean square deviation (RMSD) fluctuations compared to the squamocin-C–HER2 complex, suggesting enhanced conformational retention. Collectively, RMSF, radius of gyration, and hydrogen bond occupancy data suggest thermodynamic stability of the respective complexes. ADME and toxicity predictions indicated that annocherin possessed higher solubility and permeability, while squamocin-C exhibited greater blood–brain barrier permeability. Conclusion: Overall, this study highlights acetogenins as promising scaffolds for the rational design of novel MELK and HER2 inhibitors, offering a potential route toward targeted cancer therapeutics derived from natural products.