Identification of Novel Inhibitors for ERα Target of Breast Cancer By In Silico Approach

Background: Estrogen alpha has been recognized as a perilous factor in breast cancer cell proliferation and has been proficiently treated in breast cancer chemotherapy with the development of selective estrogen receptor modulators (SERMs). Objectives: The major aim of this study was to identify the potential inhibitors against the most influential target ERα receptor by in silico studies of 115 phytochemicals from 17 medicinal plants using in silico molecular docking studies. Methods: The molecular docking investigation was carried out by a genetic algorithm using the Auto Dock Vina program, and the validation of docking was also performed using molecular dynamic (MD) simulation by the Desmond tool of Schrödinger molecular modeling. The ADME( T) studies were performed by SWISS ADME and ProTox-II. Results: The top ten highest binding energy phytochemicals identified were amyrin acetate (- 10.7 kcal/mol), uscharine (-10.5 kcal/mol), voruscharin (-10.0 kcal/mol), cyclitols (-10.0 kcal/mol), taraxeryl acetate (-9.9 kcal/mol), amyrin (-9.9 kcal/mol), barringtogenol C (-9.9 kcal/mol), calactin (-9.9 kcal/mol), 3-beta taraxerol (-9.8 kcal/mol), and calotoxin (-9.8 kcal/mol). A molecular docking study revealed that these phytochemical constituents showed higher binding affinity compared to the reference standard tamoxifen (-6.6 kcal/mol) towards the target protein ERα. The results of MD studies showed that all four tested compounds possess comparatively stable ligand-protein complexes with ERα target as compared to the tamoxifen- ERα complex. Conclusion: Among the ten compounds, phytochemical amyrin acetate (triterpenoids) formed a more stable complex as well as exhibited greater binding affinity than standard tamoxifen. ADMET studies for the top ten phytochemicals showed a good safety profile. Additionally, these compounds are being reported for the first time in this study as possible inhibitors of ERα for the treatment of breast cancer by adopting the concept of drug repurposing. Hence, these phytochemicals can be further studied and can be used as a parent core molecule to develop novel lead molecules for breast cancer therapy.