Title: Elucidation of Agonist and Antagonist Dynamic Binding Patterns in ER-α by Integration of Molecular Docking, Molecular Dynamics Simulations and Quantum Mechanical Calculations

Journal Article · · International Journal of Molecular Sciences (Online)
 [1]; ORCiD logo [2];  [3];  [3];  [3];  [3]; ORCiD logo [3]
  1. U.S. Food and Drug Administration (FDA), Jefferson, AR (United States). National Center for Toxicological Research; OSTI
  2. U.S. Food and Drug Administration (FDA), Jefferson, AR (United States). National Center for Toxicological Research; Alagappa Univ., Karaikudi (India)
  3. U.S. Food and Drug Administration (FDA), Jefferson, AR (United States). National Center for Toxicological Research
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Estrogen receptor alpha (ERα) is a ligand-dependent transcriptional factor in the nuclear receptor superfamily. Many structures of ERα bound with agonists and antagonists have been determined. However, the dynamic binding patterns of agonists and antagonists in the binding site of ERα remains unclear. Therefore, we performed molecular docking, molecular dynamics (MD) simulations, and quantum mechanical calculations to elucidate agonist and antagonist dynamic binding patterns in ERα. 17β-estradiol (E2) and 4-hydroxytamoxifen (OHT) were docked in the ligand binding pockets of the agonist and antagonist bound ERα. The best complex conformations from molecular docking were subjected to 100 nanosecond MD simulations. Hierarchical clustering was conducted to group the structures in the trajectory from MD simulations. The representative structure from each cluster was selected to calculate the binding interaction energy value for elucidation of the dynamic binding patterns of agonists and antagonists in the binding site of ERα. The binding interaction energy analysis revealed that OHT binds ERα more tightly in the antagonist conformer, while E2 prefers the agonist conformer. The results may help identify ERα antagonists as drug candidates and facilitate risk assessment of chemicals through ER-mediated responses.

Research Organization:
Oak Ridge Inst. for Science and Education (ORISE), Oak Ridge, TN (United States); U.S. Food and Drug Administration (FDA), Jefferson, AR (United States). National Center for Toxicological Research
Sponsoring Organization:
US Food and Drug Administration (FDA); USDOE Office of Science (SC)
Grant/Contract Number:
SC0014664
OSTI ID:
1904946
Journal Information:
International Journal of Molecular Sciences (Online), Journal Name: International Journal of Molecular Sciences (Online) Journal Issue: 17 Vol. 22; ISSN IJMCFK; ISSN 1422-0067
Publisher:
MDPICopyright Statement
Country of Publication:
United States
Language:
English

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59 BASIC BIOLOGICAL SCIENCES
dynamic binding pattern
estrogen receptor
molecular docking
molecular dynamics simulations
quantum mechanical calculations