Background: Estrogen Receptors (ER) are members of the nuclear intracellular receptors family. ER once activated by estrogen, it binds to DNA via translocating into the nucleus and regulates the activity of various genes. Withaferin A (WA) - an active compound of a medicinal plant Withania somnifera was reported to be a very effective anti-cancer agent and some of the recent studies has demonstrated that WA is capable of arresting the development of breast cancer via targeting estrogen receptor.

Objective: The present study is aimed at understanding the molecular level interactions of ER and Tamoxifen in comparison to Withaferin A using In-silico approaches with emphasis on Withaferin A binding capability with ER in presence of point mutations which are causing de novo drug resistance to existing drugs like Tamoxifen.

Methods: Molecular modeling and docking studies were performed for the Tamoxifen and Withaferin A with the Estrogen receptor. Molecular docking simulations of estrogen receptor in complex with Tamoxifen and Withaferin A were also performed.

Results: Amino acid residues, Glu353, Arg394 and Leu387 was observed as crucial for binding and stabilizing the protein-ligand complex in case of Tamoxifen and Withaferin-A. The potential of Withaferin A to overcome the drug resistance caused by the mutations in estrogen receptor to the existing drugs such as Tamoxifen was demonstrated.

Conclusion: In-silico analysis has elucidated the binding mode and molecular level interactions which are expected to be of great help in further optimizing Withaferin A or design / discovery of future breast cancer inhibitors targeting estrogen receptor.

背景：雌激素受体（ER）是细胞内核受体家族的成员。雌激素一旦被雌激素激活，便通过转运进入细胞核而与DNA结合并调节各种基因的活性。Withaferin A（WA）-药用植物Withania somnifera的活性化合物据报道是一种非常有效的抗癌药，最近的一些研究表明，WA能够通过靶向雌激素受体来阻止乳腺癌的发展。

目的：本研究旨在通过计算机方法了解ER和他莫昔芬与Withaferin A的分子水平相互作用，重点是在存在点突变的情况下Withaferin A与ER的结合能力，这些突变导致对现有药物产生新的耐药性药物如他莫昔芬。

方法：对具有雌​​激素受体的他莫昔芬和Withaferin A进行了分子建模和对接研究。还进行了雌激素受体与他莫昔芬和Withaferin A配合物的分子对接模拟。

结果：在他莫昔芬和Withaferin-A的情况下，观察到氨基酸残基，Glu353，Arg394和Leu387对于结合和稳定蛋白质-配体复合物至关重要。证明了Withaferin A克服由雌激素受体突变引起的对他莫昔芬等现有药物的耐药性的潜力。

结论：计算机模拟分析已经阐明了结合模式和分子水平的相互作用，这有望对进一步优化Withaferin A或设计/发现未来靶向雌激素受体的乳腺癌抑制剂有很大帮助。