In-Silico Identification of Natural Compounds as Dual Inhibitors of Aromatase andCDK4/6: A Multi-Target Approach for ER-Positive Breast Cancer Treatment

Introduction: The diagnosis of Estrogen-positive (ER+) breast cancer remains a major challenge for postmenopausal women. The progression of this disease depends heavily on estrogen signaling, which serves as an essential target for treatment strategies. The progression of the disease and the development of resistance to treatment occur because of abnormalities in the cyclin D1-CDK4/6–Rb pathway, even though aromatase inhibitors are effective. Methods: To identify potential dual inhibitors of aromatase and CDK4/6, 170,269 natural compounds from the Asinex database were screened using multi-target virtual screening. The top hits underwent molecular docking, ADMET profiling, density functional theory (DFT) analysis, 100 ns Molecular Dynamics (MD) simulations, and MM-GBSA binding energy calculations as part of a comprehensive in silico analysis. Results: In the initial phase, 76 aromatase-targeting compounds were screened against CDK4 and CDK6. Two dual-target candidates demonstrated promising potential: LAS52119664 and BBF30702300, which showed aromatase (−8.21 kcal/mol) and CDK4 (−197.87 ± 14.09 kcal/mol) binding, and BBF30702300, which showed aromatase (−6.21 kcal/mol) and CDK6 (−110.58 ± 8.43 kcal/mol) binding. Discussion: The DFT analysis demonstrated that the HOMO-LUMO gaps were 0.184 and 0.181 eV, which indicated high reactivity. Both complexes maintained stability during a 100-nanosecond molecular dynamics simulation, as shown by their steady RMSD and RMSF values. ADMET profiling and in silico toxicity predictions confirmed the drug-like features of these compounds. ER+ breast cancer therapy may benefit from these compounds, which act as dual inhibitors. Conclusion: Both LAS52119664 and BBF30702300 emerged as novel and promising natural dual inhibitors of aromatase and CDK4/6, providing a basis for future experimental validation and the development of multitargeted therapies for ER-positive breast cancer.