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Background: Estrogen Receptors (ER) are members of the nuclear intracellular receptorsfamily. ER once activated by estrogen, it binds to DNA via translocating into the nucleus and regulatesthe activity of various genes. Withaferin A (WA) - an active compound of a medicinal plant Withaniasomnifera was reported to be a very effective anti-cancer agent and some of the recent studies hasdemonstrated that WA is capable of arresting the development of breast cancer via targeting estrogenreceptor. Objective: The present study is aimed at understanding the molecular level interactions of ER and Tamoxifenin comparison to Withaferin A using In-silico approaches with emphasis on Withaferin Abinding capability with ER in presence of point mutations which are causing de novo drug resistance toexisting drugs like Tamoxifen. Methods: Molecular modeling and docking studies were performed for the Tamoxifen and WithaferinA with the Estrogen receptor. Molecular docking simulations of estrogen receptor in complex withTamoxifen and Withaferin A were also performed. Results: Amino acid residues, Glu353, Arg394 and Leu387 was observed as crucial for binding andstabilizing the protein-ligand complex in case of Tamoxifen and Withaferin-A. The potential ofWithaferin A to overcome the drug resistance caused by the mutations in estrogen receptor to the existingdrugs such as Tamoxifen was demonstrated. Conclusion: In-silico analysis has elucidated the binding mode and molecular level interactions whichare expected to be of great help in further optimizing Withaferin A or design / discovery of futurebreast cancer inhibitors targeting estrogen receptor.