Virtual Docking Screening and QSAR Studies to Explore PI3K and mTOR Inhibitors Acting on AKT in Cancers

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Abstract

The PI3K / AKT / mTOR pathway is an important regulator of a wide range of cellular processes including survival, proliferation, growth, metabolism, angiogenesis and metastasis. PI3K induces translocation of Ser / Thr Akt kinase, Akt is activated by PDK1 and mTOR2-dependent phosphorylations. 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 common AKT / mTOR and AKT / PI3K competitor ATP inhibitors we performed a 2D AKT-SAR model to predict the bioactivity of PI3K and mTOR inhibitors on AKT, the interaction of the best inhibitors was evaluated by docking analysis and compared to that of GSK690693 and Ipatasertib. An AKT-SAR model with a correlation coefficient (R2) of 0.85212 and an RMSE of 0.09266 was obtained, which was validated and evaluated by a cross-validation method LOO, the most predicted inhibitors of PI3K and mTOR respectively PIC50 activities between [9.30 - 8.54], and [9.79 - 8.91]. After docking and several comparisons, inhibitors with better predictions showed better affinity and interaction with AKT compared to GSK690693 and Ipatasertib. We therefore found that 8 PI3K inhibitors and 11 mTOR inhibitors met the Lipinski and Veber criteria and could be future drugs.

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