Identification of novel HER2 ınhibitors: potential therapeutics for breast cancer

Abstract

Human epidermal growth factor receptor-2 (HER2) is a tyrosine kinase receptor involved in cell growth and differentiation. Targeting HER2 is a critical strategy in HER2-positive breast cancer treatment. Despite advancements in HER2-targeted therapies, drug resistance and side effects remain significant challenges. Therefore, identifying novel HER2 inhibitors with the potential to overcome resistance mechanisms while maintaining favorable drug-like properties is essential. Identifying novel HER2 inhibitors with high binding affinity and favorable drug-like properties is essential for overcoming these limitations. This study employed molecular docking and molecular dynamics simulations to evaluate the binding potential of plant-derived and synthetic compounds against HER2. The most promising candidates were further analyzed using ADMET profiling and binding free energy calculations to assess their drug-likeness and binding free energy. Among the tested compounds, axitinib, prunetin, and silymarin demonstrated strong HER2-binding affinities comparable to established inhibitors such as TAK-285 and lapatinib. Molecular dynamics simulations revealed that prunetin formed the most stable HER2-ligand complex, while axitinib exhibited the lowest binding free energy, indicating a strong interaction potential. ADMET analysis confirmed axitinib and prunetin as favorable drug candidates, whereas silymarin exhibited lower intestinal absorption. In conclusion, axitinib and prunetin emerged as promising HER2 inhibitors that may offer therapeutic advantages by addressing both drug resistance and toxicity concerns in HER2-positive breast cancer treatment. Prunetin, with its lower toxicity and higher stability, presents a safer therapeutic option, whereas axitinib offers high binding affinity. These findings suggest that these compounds could help overcome resistance and side effects associated with current HER2-targeted therapies.