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

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...

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Veröffentlicht in:Molecular diversity 2023-06, Vol.27 (3), p.1141-1162
Hauptverfasser: Rasul, Hezha O., Aziz, Bakhtyar K., Ghafour, Dlzar D., Kivrak, Arif
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container_title Molecular diversity
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creator Rasul, Hezha O.
Aziz, Bakhtyar K.
Ghafour, Dlzar D.
Kivrak, Arif
description 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. Graphical abstract
doi_str_mv 10.1007/s11030-022-10475-9
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subjects Biochemistry
Biomedical and Life Sciences
Breast cancer
Breast Neoplasms - drug therapy
Cichorium intybus
Drug development
Female
Humans
Life Sciences
Ligands
Molecular Docking Simulation
Molecular Dynamics Simulation
MTOR Inhibitors
Organic Chemistry
Original Article
Pharmacy
Polymer Sciences
Proteins
Sirolimus - therapeutic use
TOR Serine-Threonine Kinases
title 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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