QSAR modeling and structure based virtual screening of new PI3K/mTOR inhibitors as potential anticancer agents

Phosphatidylinositol-3-kinase (PI3K) / mammalian target of rapamycin (mTOR) kinases belong to the phosphatidylinositol-3-kinase-related kinase (PIKK) family of kinases. Dysregulation of PI3K/mTOR signaling pathway is often detected in various types of malignancies and is correlated with a poor prognosis. PI3K and mTOR share considerable homology in the structure of their active sites and rational advantages of dual inhibition of PI3K/mTOR are known. In order to identify the most important structural determinants that influence antiproliferative activity, 3D-QSAR (quantitative structure activity relationship) studies were performed on two groups of structurally diverse PI3K/mTOR inhibitors. Created QSAR models passed internal and external validation allowing the reliable activity prediction of new PI3K/mTOR inhibitors that were designed based on the obtained 3D-pharmacophores. Initial pool of designed compounds was subjected to structure based virtual screening in order to select the best candidates. Results of this study may be very helpful in further discovery of selective PI3K/mTOR dual inhibitors as novel antineoplastics