Virtual docking screening and QSAR studies to explore AKT and mTOR inhibitors acting on PI3K in cancers.
| Autor: | Kandoussi I; Biotechnology Laboratory (MedBiotech), Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco., Benherrif O; Biotechnology Laboratory (MedBiotech), Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco., Lakhlili W; Biotechnology Laboratory (MedBiotech), Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco., Taoufik J; Laboratory of Medicinal Chemistry, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco., Ibrahimi A; Biotechnology Laboratory (MedBiotech), Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco. |
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| Jazyk: | angličtina |
| Zdroj: | Contemporary oncology (Poznan, Poland) [Contemp Oncol (Pozn)] 2020; Vol. 24 (1), pp. 5-12. Date of Electronic Publication: 2020 Feb 26. |
| DOI: | 10.5114/wo.2020.93334 |
| Abstrakt: | 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. Competing Interests: The authors declare no conflict of interest. (Copyright: © 2020 Termedia Sp. z o. o.) |
| Databáze: | MEDLINE |
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