Dual Targeting of EGFR and Estrogen Receptor α by Plant-Derived Thymoquinone: An in Silico Docking, ADMET, and Molecular Dynamics Study or Breast Cancer Therapy

Background: Breast cancer is still among the most common causes of cancer mortality on the global scale due to the sophisticated set of molecular mechanisms that involve the targets like estrogen receptor alpha (ER 2) and epidermal growth factor receptor (EGFR). Although tamoxifen is clinically successful, therapeutic resistance and side effects require the search of safer and multi-targeted analogs. Natural compounds, especially phyto chemical, have become an attractive candidate because of their multi-pathway modulation and less toxic. Purpose: This paper was designed to assess the dual inhibition ability of Nigella sativa finding, thymoquinone, against the ERa and EGFR receptors in an integrated in silico method, comprising of molecular docking, ADMET profiling, and molecular dynamics simulation in the presence of tamoxifen as a control drug. Methods: AutoDock Vina was used to do molecular docking on EGFR (PDB ID: 1M17) and ER (PDB ID: 3ERT). Interactions of the ligands and proteins were evaluated with the help of PyMOL and Discovery Studio. The SwissADME and pkCSM tools were used to predict the pharmacokinetic and toxicity properties. Simulations of molecular dynamics were performed in 50ns of the desmond package to test the stability of the structure and the persistence of binding. Findings: Thymoquinone had moderate affinity to EGFR ( -4.881 kcal/mol), and was in stable interactions with essential residues, including GLU804, TYR777 and TRP739 by hydrophobic and - contacts. Thymoquinone in ERa showed a structurally stable binding mode that is hydrogen bonded with LYS529 and electrostatically bonded with ARG394 and ASP351 at a relatively low energy of binding. In comparative analysis, tamoxifen proved to be in a greater extent of interaction with ERa and EGFR, which confirmed the docking protocol. Through the ADMET profiling, it was found that thymoquinone has better drug-likeness, better solubility, low toxicity and less hERG inhibition than tamoxifen which has high lipophilicity, high plasma protein binding and high risks of toxicity. The stability of the ligand-protein complexes was confirmed by the simulations of molecular dynamics. Conclusion: Thymoquinone has shown good dual-target interactions with ER and EGFR with good pharmacokinetic and safety profiles. The binding affinity of it is lower than tamoxifen, but its balanced ADMET properties and multi-target potential indicate the potential of the compound as a natural lead compound to be further developed in terms of breast cancer treatment.