Mammalian target of rapamycin (mTOR) is a promising target for the development of anticancer medicines. Here, we report the first example for a successful application of the structure-based virtual screening to identify new mTOR inhibitors. Using the scoring function improved by implementing the ligand solvation effects on protein-ligand association, six novel mTOR inhibitors are found with IC50 values ranging from 8 to 60 μM. Because these new inhibitors are also computationally screened for having desirable physicochemical properties as a drug candidate, they deserve consideration for further development by structure-activity relationship studies to optimize the inhibitory and anticancer activities. Structural features relevant to the stabilization of the inhibitors in the ATP-binding site of mTOR are addressed in detail.
Keywords: Anticancer agents; Docking; Kinase inhibitor; Virtual screening; mTOR.
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