Abstract
Estrogen receptor α (ER α) is an important therapeutic target in the regulation of ligand dependent signaling in breast cancer. The current study investigates the anti-estrogenic potential of the Diarylheptanoid, 5-hydroxy-7-(4-hydroxy-3 methoxyphenyl)-1-phenyl-3-heptanone (DAH) in silico. Rigid Docking analysis of DAH at the ligand binding domain (LBD) of ER α showed hydrogen bond interactions with Arg394 and Glu353 at the active site, similar to the positive controls 4-Hydroxy Tamoxifen (4-OHT) and Fulvestrant (FUL). The protein and the protein–DAH complexes were further analyzed using molecular dynamics simulations for a time scale of 50 ns using GROMACS. Root mean square fluctuation (RMSF) analysis showed large fluctuations at the N-terminal region of Helices (H) 3, 9 and at the C-terminal region of H11, which could be involved in the antagonistic conformational change. Interestingly, H12 appeared to move away from the ligand binding pocket and occupy the co-activator binding groove at the LBD of ER α. Secondary structure analysis of the protein upon binding of DAH and CUR showed structural change from α-helix to Turn conformation at H4. We hypothesize that this structural change at H4, similar to the positive control, could hinder the activity of AF-2 by blocking the binding of co-activator. These conformational changes in ER α indicate an anti-estrogenic and therapeutic potential of the DAH.
Abbreviations:
- AF – Activation Factor
- A – Agonist
- AT – Antagonist
- AIB-1 – Amplified in Breast 1
- DAH – Diarylheptanoid
- DES – Diethylstilbestrol
- CUR – Curcumin
- ER α – Estrogen Receptor Alpha
- ER α – Estrogen Receptor Beta
- ESR 1 – Estrogen Receptor 1
- ESR 2 – Estrogen Receptor 2
- ERE – Estrogen Response Element
- E2 – 17β Estradiol
- FUL – Fulvestrant
- LBD – Ligand Binding Domain
- SERD – Selective Estrogen Receptor Downregulator
- SERM – Selective Estrogen Receptor Modulator
- SRC-1 – Steroid Receptor Co-activator -1
- 4-OHT – 4-Hydroxy Tamoxifen
Acknowledgments
The authors acknowledge support from departmental level assistance programmes DBT – BUILDER (BT/PR12153/INF/22/200/2014), DBT-DIC-BTIS and UGC-SAP-DSA, Government of India.