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  1. Article ; Online: Virtual docking screening and QSAR studies to explore AKT and mTOR inhibitors acting on PI3K in cancers

    Ilham Kandoussi / Oussama Benherrif / Wiame Lakhlili / Jamal Taoufik / Azeddine Ibrahimi

    Contemporary Oncology, Vol 24, Iss 1, Pp 5-

    2020  Volume 12

    Abstract: The phosphoinositide 3-kinase (PI3K) pathway is an important regulator of cell proliferation and metabolism. PI3K activation initiates a signal transduction cascade, of which the major effectors are the kinases AKT and mTOR. Aberrant activation of the ... ...

    Abstract The phosphoinositide 3-kinase (PI3K) pathway is an important regulator of cell proliferation and metabolism. PI3K activation initiates a signal transduction cascade, of which the major effectors are the kinases AKT and mTOR. Aberrant activation of the PI3K/AKT/mTOR pathway is frequently observed in many human malignancies and the combination of compounds simultaneously targeting different related molecules in the PI3K/AKT/mTOR pathway leads to synergistic activity. To explore the competing common ATP inhibitors PI3K/AKT and PI3K/mTOR we developed a model PI3K-SAR 2D which made it possible to predict the bioactivity of inhibitors of AKT and mTOR towards PI3K; the interaction of the best inhibitors was evaluated by docking analysis and compared to that of dactolisib and pictilisib. A PI3K-SAR model with a correlation coefficient (R2) of 0.81706 and an RMSE of 0.16029 was obtained, which was validated and evaluated by a cross-validation method, LOO. The most predicted AKT and mTOR inhibitors present respectively pIC50 activities between 9.26–9.93 and 9.59–9.87. After docking and several comparisons, inhibitors with better predictions showed better affinity and interaction with PI3K compared to pictilisib and dactolisib, so we found that 4 inhibitors of AKT and 14 mTOR inhibitors met the criteria of Lipinski and Veber and could be future drugs.
    Keywords qsar ; virtual screening ; pi3k/akt/mtor ; docking ; dual atp inhibitors ; Medicine ; R
    Subject code 572
    Language English
    Publishing date 2020-02-01T00:00:00Z
    Publisher Termedia Publishing House
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Curcumin-Synthetic Analogs Library Screening by Docking and Quantitative Structure-Activity Relationship Studies for AXL Tyrosine Kinase Inhibition in Cancers.

    Ghrifi, Fatima / Allam, Loubna / Wiame, Lakhlili / Ibrahimi, Azeddine

    Journal of computational biology : a journal of computational molecular cell biology

    2019  Volume 26, Issue 10, Page(s) 1156–1167

    Abstract: AXL is an important drug target for cancers. Two-dimensional quantitative structure-activity relationship (2D-QSAR) tests were performed to elucidate a relationship between molecular structures and the activity of a series of 400 curcumin derivatives ... ...

    Abstract AXL is an important drug target for cancers. Two-dimensional quantitative structure-activity relationship (2D-QSAR) tests were performed to elucidate a relationship between molecular structures and the activity of a series of 400 curcumin derivatives subjected to AXL kinase by ATP competition in the catalytic site. The partial least square regression method implanted in molecular operating environment software was applied to develop QSAR models, which were further validated for statistical significance by internal and external validation. The best model has proven to be statistically robust with a good predictive correlation of
    MeSH term(s) Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Curcumin/analogs & derivatives ; Curcumin/pharmacology ; Humans ; Molecular Docking Simulation ; Neoplasms/drug therapy ; Neoplasms/enzymology ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins/antagonists & inhibitors ; Proto-Oncogene Proteins/metabolism ; Quantitative Structure-Activity Relationship ; Receptor Protein-Tyrosine Kinases/antagonists & inhibitors ; Receptor Protein-Tyrosine Kinases/metabolism
    Chemical Substances Antineoplastic Agents ; Protein Kinase Inhibitors ; Proto-Oncogene Proteins ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; axl receptor tyrosine kinase (EC 2.7.10.1) ; Curcumin (IT942ZTH98)
    Language English
    Publishing date 2019-06-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2030900-4
    ISSN 1557-8666 ; 1066-5277
    ISSN (online) 1557-8666
    ISSN 1066-5277
    DOI 10.1089/cmb.2019.0052
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Molecular screening and docking analysis of LMTK3and AKT1 combined inhibitors.

    Allam, Loubna / Fatima, Ghrifi / Wiame, Lakhlili / Hamid, El Amri / Azeddine, Ibrahim

    Bioinformation

    2018  Volume 14, Issue 9, Page(s) 499–503

    Abstract: The abnormal activation of AKT/mTOR signaling pathway and overexpression of LMTK3, are the main factors involved in the generation of drug resistance. Therefore, the use of computer-aided drug design in the inhibitors discovery offers an advantage to ... ...

    Abstract The abnormal activation of AKT/mTOR signaling pathway and overexpression of LMTK3, are the main factors involved in the generation of drug resistance. Therefore, the use of computer-aided drug design in the inhibitors discovery offers an advantage to provide new candidates for the treatment of this resistance. We realised the virtual screening and molecular docking of AKT1 and LMTK3 proteins by the Dockblaster server. In addition, with abundance of candidates under development for AKT1 kinase, we have also conducted a Quantitative Structure-Activity Relationship (QSAR) study based on these compounds, in order to design more active compounds and predict their activity for development of a new inhibitor of AKT1. QSAR tests were performed for AKT1 using the Partial Least Squares method with a correlation coefficient of R2=0.8062 and a cross-validation of q2=0.6995. This test has selected five compounds as competitive inhibitors-AKT1-ATP with a better biological activities. In parallel the molecular screening has selected five other compounds as competitive ATP-inhibitors of LMTK3. One of them is a common inhibitor with AKT1, and it is marketed as a moderate to severe pain therapy. The ADME predictions confirmed the inhibitors pharmacological activity of these compounds for potential consideration as drug candidates.
    Language English
    Publishing date 2018-12-09
    Publishing country Singapore
    Document type Journal Article
    ZDB-ID 2203786-X
    ISSN 0973-2063
    ISSN 0973-2063
    DOI 10.6026/97320630014499
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

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