Title:In Silico Elucidation of the Plausible Inhibitory Potential of Withaferin A of Withania Somnifera Medicinal Herb Against Breast Cancer Targeting Estrogen Receptor
VOLUME: 21 ISSUE: 9
Author(s):Mohammad A. Ali*, Mohammad Abul Farah*, Khalid M. Al-Anazi, Syed H. Basha, Fang Bai, Joongku Lee, Fahad M.A. Al-Hemaid, Ahmed H. Mahmoud and Waleed A.Q. Hailan
Affiliation:Department of Botany and Microbiology, College of Science, King Saud University, Riyadh- 11451, Department of Zoology, College of Science, King Saud University, Riyadh- 11451, Department of Zoology, College of Science, King Saud University, Riyadh- 11451, Innovative Informatica Technologies, HIG, HUDA, Mayuri Nagar, Miyapur, Hyderabad, 500 049, Center for Theoretical Biological Physics, Rice University, Houston, TX 77005, Department of Environment and Forest Resources, Chungnam National University, Daehak-ro, Yuseong-gu, Daejeon, Department of Botany and Microbiology, College of Science, King Saud University, Riyadh- 11451, Department of Zoology, College of Science, King Saud University, Riyadh- 11451, Department of Zoology, College of Science, King Saud University, Riyadh- 11451
Keywords:Withania Somnifera, estrogen receptor, tamoxifen, withaferin A, molecular docking, molecular dynamics simulations.
Abstract:
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.
