Estrogen Receptor Alpha Binders for Hormone-Dependent Forms of Breast Cancer: e-QSAR and Molecular Docking Supported by X-ray Resolved Structures

H. Masand, Vijay and A. Al-Hussain, Sami and Y. Alzahrani, Abdullah and A. Al-Mutairi, Aamal and A. Hussien, Rania and Samad, Abdul and E. A. Zaki, Magdi (2024) Estrogen Receptor Alpha Binders for Hormone-Dependent Forms of Breast Cancer: e-QSAR and Molecular Docking Supported by X-ray Resolved Structures. ACS Omega, 9 (14). pp. 16759-16774. ISSN 2470-1343

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Abstract

Cancer, a life-disturbing and lethal disease with a high global impact, causes significant economic, social, and health challenges. Breast cancer refers to the abnormal growth of cells originating from breast tissues. Hormone-dependent forms of breast cancer, such as those influenced by estrogen, prompt the exploration of estrogen receptors as targets for potential therapeutic interventions. In this study, we conducted e-QSAR molecular docking and molecular dynamics analyses on a diverse set of inhibitors targeting estrogen receptor alpha (ER-α). The e-QSAR model is based on a genetic algorithm combined with multilinear regression analysis. The newly developed model possesses a balance between predictive accuracy and mechanistic insights adhering to the OECD guidelines. The e-QSAR model pointed out that sp2-hybridized carbon and nitrogen atoms are important atoms governing binding profiles. In addition, a specific combination of H-bond donors and acceptors with carbon, nitrogen, and ring sulfur atoms also plays a crucial role. The results are supported by molecular docking, MD simulations, and X-ray-resolved structures. The novel results could be useful for future drug development for ER-α.

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