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Discovery of potential mTOR inhibitors from Cichorium intybus to find new candidate drugs targeting the pathological protein related to the breast cancer: an integrated computational approach

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Abstract

Breast cancer is the most common malignancy among women. It is a complex condition with many subtypes based on the hormone receptor. The mammalian target of the rapamycin (mTOR) pathway regulates cell survival, metabolism, growth, and protein synthesis in response to upstream signals in both normal physiological and pathological situations, primarily in cancer. The objective of this study was to screen for a potential target to inhibit the mTOR using a variety of inhibitors derived from Cichorium intybus and to identify the one with the highest binding affinity for the receptor protein. Initially, AutoDock Vina was used to perform structure-based virtual screening, as protein-like interactions are critical in drug development. For the comparative analysis, 110 components of Cichorium intybus were employed and ten FDA-approved anticancer medicines, including everolimus, an mTOR inhibitor. Further, the drug-likeness and ADMET properties were investigated to evaluate the anti-breast cancer activity by applying Lipinski's rule of five to the selected molecules. The promising candidates were then subjected to three replica molecular dynamics simulations run for 100 ns, followed by binding free energy estimation using MM-GBSA. The data were analyzed using root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), and protein–ligand interactions to determine the stability of the protein–ligand complex. Based on the results, taraxerone (98) revealed optimum binding affinities with mTOR, followed by stigmasterol (110) and rutin (104), which compared favorably to the control compounds. Subsequently, bioactive compounds derived from Cichorium intybus may serve as lead molecules for developing potent and effective mTOR inhibitors to treat breast cancer.

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All data generated during this study are included in supplementary information files.

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Acknowledgements

The authors would like to express their gratitude to Charmo University and Komar University of Science and Technology for their ongoing assistance and facilities in carrying out this research.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, College of Medicals and Applied Sciences, Charmo University, Peshawa Street, Chamchamal, Sulaimani, 46023, Iraq

    Hezha O. Rasul

  2. Department of Nanoscience and Applied Chemistry, College of Medicals and Applied Sciences, Charmo University, Peshawa Street, Chamchamal, Sulaimani, 46023, Iraq

    Bakhtyar K. Aziz

  3. Department of Medical Laboratory Science, College of Science, Komar University of Science and Technology, Sulaimani, 46001, Iraq

    Dlzar D. Ghafour

  4. Department of Chemistry, College of Science, University of Sulaimani, Sulaimani, 46001, Iraq

    Dlzar D. Ghafour

  5. Department of Chemistry, Faculty of Sciences and Arts, Eskisehir Osmangazi University, Eskişehir, 26040, Turkey

    Arif Kivrak

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  1. Hezha O. Rasul
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  2. Bakhtyar K. Aziz
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  3. Dlzar D. Ghafour
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  4. Arif Kivrak
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Contributions

Hezha O. Rasul contributed to conceptualization, methodology, software, data curation, and writing. Bakhtyar K. Aziz contributed to supervision, software, and validation Dlzar D. Ghafour contributed to writing, review and editing, visualization, resources. Arif Kivrak contributed to validation, writing–review and editing.

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Correspondence to Hezha O. Rasul.

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Rasul, H.O., Aziz, B.K., Ghafour, D.D. et al. Discovery of potential mTOR inhibitors from Cichorium intybus to find new candidate drugs targeting the pathological protein related to the breast cancer: an integrated computational approach. Mol Divers 27, 1141–1162 (2023). https://doi.org/10.1007/s11030-022-10475-9

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  • DOI: https://doi.org/10.1007/s11030-022-10475-9

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