Virtual docking screening and quantitative structure-activity relationship studies to explore AKT and PI3K inhibitors acting on mTOR in cancers by theoretical biology and medical modeling

Ilham Kandoussi; Hanane Abbou; Ghyzlane EL Haddoumi; Mariam Mansouri; Lahcen Belyamani; Azeddine Ibrahimi

doi:10.5114/wo.2023.133709

eISSN: 1897-4309
ISSN: 1428-2526

Contemporary Oncology/Współczesna Onkologia

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3/2023
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abstract:

Original paper

Virtual docking screening and quantitative structure-activity relationship studies to explore AKT and PI3K inhibitors acting on mTOR in cancers by theoretical biology and medical modeling

Ilham Kandoussi

^{1, 2}

,

Hanane Abbou

^{1, 2}

,

Ghyzlane EL Haddoumi

^{1, 2}

,

Mariam Mansouri

^{1, 2}

,

Lahcen Belyamani

^{1, 2, 3}

,

Azeddine Ibrahimi

^{1, 2}

Biotechnology Laboratory (MedBiotech), Bioinova Research Center, Rabat Medical & Pharmacy School, Mohammed V University in Rabat, Morocco
Centre Mohammed VI de la Recherche et de l’Innovation, Rabat, Morocco
Emergency Department, Military Hospital Mohammed V, Rabat, Morocco

Contemp Oncol (Pozn) 2023; 27 (3): 155–162

DOI: https://doi.org/10.5114/wo.2023.133709

Online publish date: 2023/12/13

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AMA

Kandoussi I, Abbou H, Haddoumi G, Mansouri M, Belyamani L, Ibrahimi A. Virtual docking screening and quantitative structure-activity relationship studies to explore AKT and PI3K inhibitors acting on mTOR in cancers by theoretical biology and medical modeling. Contemporary Oncology/Współczesna Onkologia. 2023;27(3):155-162. doi:10.5114/wo.2023.133709.

APA

Kandoussi, I., Abbou, H., Haddoumi, G., Mansouri, M., Belyamani, L.,  & Ibrahimi, A. (2023). Virtual docking screening and quantitative structure-activity relationship studies to explore AKT and PI3K inhibitors acting on mTOR in cancers by theoretical biology and medical modeling. Contemporary Oncology/Współczesna Onkologia, 27(3), 155-162. https://doi.org/10.5114/wo.2023.133709

Chicago

Kandoussi, Ilham, Hanane Abbou, Ghyzlane EL Haddoumi, Mariam Mansouri, Lahcen Belyamani,  and Azeddine Ibrahimi. 2023. "Virtual docking screening and quantitative structure-activity relationship studies to explore AKT and PI3K inhibitors acting on mTOR in cancers by theoretical biology and medical modeling". Contemporary Oncology/Współczesna Onkologia 27 (3): 155-162. doi:10.5114/wo.2023.133709.

Harvard

Kandoussi, I., Abbou, H., Haddoumi, G., Mansouri, M., Belyamani, L.,  and Ibrahimi, A. (2023). Virtual docking screening and quantitative structure-activity relationship studies to explore AKT and PI3K inhibitors acting on mTOR in cancers by theoretical biology and medical modeling. Contemporary Oncology/Współczesna Onkologia, 27(3), pp.155-162. https://doi.org/10.5114/wo.2023.133709

MLA

Kandoussi, Ilham et al. "Virtual docking screening and quantitative structure-activity relationship studies to explore AKT and PI3K inhibitors acting on mTOR in cancers by theoretical biology and medical modeling." Contemporary Oncology/Współczesna Onkologia, vol. 27, no. 3, 2023, pp. 155-162. doi:10.5114/wo.2023.133709.

Vancouver

Kandoussi I, Abbou H, Haddoumi G, Mansouri M, Belyamani L, Ibrahimi A. Virtual docking screening and quantitative structure-activity relationship studies to explore AKT and PI3K inhibitors acting on mTOR in cancers by theoretical biology and medical modeling. Contemporary Oncology/Współczesna Onkologia. 2023;27(3):155-162. doi:10.5114/wo.2023.133709.

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Introduction:
The mechanistic target of rapamycin (mTOR) coordinates the growth and metabolism of eukaryotic cells with a central role in the regulation of many fundamental cellular processes. It is strongly connected to phosphatidylinositol 3-kinase (PI3K) and AKT signaling. Activation of the PI3K/AKT/mTOR pathway leads to a profound disruption in the control of cell growth and survival, which ultimately leads to competitive growth advantage, metastatic competence, angiogenesis and therapeutic resistance.

Material and methods:
To explore the common competitive adenosine triphosphate (ATP) inhibitors PI3K/AKT and PI3K/mTOR, we built a 2D mTOR-SAR model that predicted the bioactivity of AKT and PI3K inhibitors towards mTOR. The interaction of the best inhibitors was evaluated by docking analysis and compared to that of the standard AZ8055 and XL388 inhibitors.

Results:
A mechanistic target of rapamycin-quantitative structure-activity relationship (mTOR-QSAR) model with a correlation coefficient (R2) of 0.80813 and a root mean square error of 0.17756 was obtained, validated and evaluated by a cross-validation leave-one-out method. The best predicted AKT and PI3K inhibitor pIC50 activities were 9.36–9.95 and 9.23–9.87 respectively.

Conclusions:
After docking and several comparisons, the inhibitors with better predictions showed better affinity and interaction with mTOR compared to AZ8055 and XL388, so we have found that 2 AKT inhibitors and 9 mTOR inhibitors met the Lipinski and Veber criteria and could be future drugs.

keywords:

Virtual docking screening and quantitative structure-activity relationship studies to explore AKT and PI3K inhibitors acting on mTOR in cancers by theoretical biology and medical modeling

Ilham Kandoussi 1, 2 , Hanane Abbou 1, 2 , Ghyzlane EL Haddoumi 1, 2 , Mariam Mansouri 1, 2 , Lahcen Belyamani 1, 2, 3 , Azeddine Ibrahimi 1, 2

QSAR, virtual screening, PI3K/AKT/mTOR, docking, dual ATP inhibitors

Ilham Kandoussi

^{1, 2}

,

Hanane Abbou

^{1, 2}

,

Ghyzlane EL Haddoumi

^{1, 2}

,

Mariam Mansouri

^{1, 2}

,

Lahcen Belyamani

^{1, 2, 3}

,

Azeddine Ibrahimi

^{1, 2}